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Sample records for 8-phenylxanthine derivatives antagonist

  1. Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists.

    PubMed

    Nitta, Aiko; Iura, Yosuke; Inoue, Hideki; Sato, Ippei; Morihira, Koichiro; Kubota, Hirokazu; Morokata, Tatsuaki; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-ichi; Imaoka, Takayuki; Takahashi, Toshiya

    2012-11-15

    Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist.

  2. N-Arylpiperazine-1-carboxamide derivatives: a novel series of orally active nonsteroidal androgen receptor antagonists.

    PubMed

    Kinoyama, Isao; Taniguchi, Nobuaki; Kawaminami, Eiji; Nozawa, Eisuke; Koutoku, Hiroshi; Furutani, Takashi; Kudoh, Masafumi; Okada, Minoru

    2005-04-01

    A novel series of N-arylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic properties were evaluated. Reporter assays indicated that trans-2,5-dimethylpiperazine derivatives are potent AR antagonists, and in this series trans-N-4-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide (18 g, YM-175735) exhibited the most potent antiandrogenic activity. Compared to bicalutamide, YM-175735 is an approximately 4-fold stronger AR antagonist and has slightly increased antiandrogenic activity, suggesting that YM-175735 may be useful in the treatment of prostate cancer.

  3. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    PubMed

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

  4. Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake.

    PubMed

    Manca, Ilaria; Mastinu, Andrea; Olimpieri, Francesca; Falzoi, Matteo; Sani, Monica; Ruiu, Stefania; Loriga, Giovanni; Volonterio, Alessandro; Tambaro, Simone; Bottazzi, Mirko Emilio Heiner; Zanda, Matteo; Pinna, Gérard Aimè; Lazzari, Paolo

    2013-04-01

    In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.

  5. Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists.

    PubMed

    Nitta, Aiko; Iura, Yosuke; Tomioka, Hiroki; Sato, Ippei; Morihira, Koichiro; Kubota, Hirokazu; Morokata, Tatsuaki; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-ichi; Imaoka, Takayuki; Takahashi, Toshiya

    2012-08-01

    The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.

  6. Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

    PubMed

    Sasmal, Sanjita; Balaji, Gade; Kanna Reddy, Hariprasada R; Balasubrahmanyam, D; Srinivas, Gujjary; Kyasa, Shivakumar; Sasmal, Pradip K; Khanna, Ish; Talwar, Rashmi; Suresh, J; Jadhav, Vikram P; Muzeeb, Syed; Shashikumar, Dhanya; Harinder Reddy, K; Sebastian, V J; Frimurer, Thomas M; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas

    2012-05-01

    Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

  7. Synthesis of Arylpiperazine Derivatives As Protease Activated Receptor 1 Antagonists And Their Evaluation As Antiproliferative Agents.

    PubMed

    Zotti, Andrea Ilaria; Di Gennaro, Elena; Corvino, Angela; Frecentese, Francesco; Magli, Elisa; Perissutti, Elisa; Cirino, Giuseppe; Roviezzo, Fiorentina; Terranova-Barberio, Manuela; Iannelli, Federica; Caliendo, Giuseppe; Santagada, Vincenzo; Fiorino, Ferdinando; Budillon, Alfredo; Severino, Beatrice

    2016-09-26

    Protease activated receptor-1 (PAR1) is a G-coupled receptor activated by α-thrombin and other proteases. Several reports demonstrate PAR1 involvement in tumorigenesis and tumor progression. In order to investigate on potential use of PAR1 antagonists as antiproliferative agents, we have identified a series of arylpiperazine derivatives acting as PAR1 antagonists; the selected molecules have been evaluated for their antiproliferative properties. All the compounds inhibited the growth of a panel of cell lines expressing PAR1; two of them, compounds 13 and 15, were able to inhibit, in a dose dependent manner, the growth of the selected cell lines with the lowest IC50 values, and were further characterized to define the mechanism responsible for the observed antiproliferative effect. This study directed us to the identification of two interesting leads that may help to further validate PAR1 as an important therapeutic target for cancer treatment.

  8. Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists.

    PubMed

    Łazewska, Dorota; Ligneau, Xavier; Schwartz, Jean-Charles; Schunack, Walter; Stark, Holger; Kieć-Kononowicz, Katarzyna

    2006-05-15

    A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different methods. The ethers obtained were evaluated for their affinities at recombinant human histamine H3 receptor, stably expressed in CHO-K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly potent and orally available histamine H3 receptor antagonists. The most potent antagonists in this series have been in vitro the 4-(1,1-dimethylpropyl)phenyl ether 19 (hH3R K(i) = 8.4 nM) and in vivo the simple ethyl ether 2 (ED50 = 1.0mg/kg).

  9. Synthesis and pharmacological evaluation of indolinone derivatives as novel ghrelin receptor antagonists.

    PubMed

    Puleo, Letizia; Marini, Pietro; Avallone, Roberta; Zanchet, Marco; Bandiera, Silvio; Baroni, Marco; Croci, Tiziano

    2012-09-15

    The ghrelin receptor is a G-protein-coupled receptor (GPCR) widely expressed in the brain, stomach and the intestine. It was firstly identified during studies aimed to find synthetic modulators of growth hormone (GH) secretion. GHSR and its endogenous ligand ghrelin were found to be involved in hunger response. Through food intake regulation, they could affect body weight and adiposity. Thus GHSR antagonists rapidly became an attractive target to treat obesity and feeding disorders. In this study we describe the biological properties of new indolinone derivatives identified as a new, chiral class of ghrelin antagonists. Their synthesis as well as the structure-activity relationship will be discussed herein. The in vitro identified compound 14f was a potent GHSR1a antagonist (IC(50) = 7 nM). When tested in vivo, on gastric emptying model, 14f showed an inhibitory intrinsic effect when given alone and it dose dependently inhibited ghrelin stimulation. Compound 14f also reduced food intake stimulated both by fasting condition (high level of endogenous ghrelin) and by icv ghrelin. Moreover this compound improved glucose tolerance in ipGTT test.

  10. Indole-3-piperazinyl derivatives: novel chemical class of 5-HT(6) receptor antagonists.

    PubMed

    Nirogi, Ramakrishna V S; Deshpande, Amol D; Kambhampati, Ramasastri; Badange, Rajesh Kumar; Kota, Laxman; Daulatabad, Anand V; Shinde, Anil K; Ahmad, Ishtiyaque; Kandikere, Vishwottam; Jayarajan, Pradeep; Dubey, P K

    2011-01-01

    N(1)-Arylsulfonyl-3-piperazinyl indole derivatives were designed and identified as a novel class of 5-HT(6) receptors ligands. All the compounds have high affinity and antagonist activity towards 5-HT(6) receptor. The compound 7a (K(i) = 3.4 nM, functional assay IC(50) = 310 nM) shows enhanced cognitive effect when tested in NORT and Morris water maze models. Synthesis, SAR and PK profile of these novel compounds constitute the subject matter of this Letter.

  11. Vaninolol: a new selective beta 1-adrenoceptor antagonist derived from vanillin.

    PubMed

    Wu, B N; Hwang, T L; Liao, C F; Chen, I J

    1994-07-05

    The beta-adrenoceptor blocking properties of vaninolol ((+/-)4-[4'-(2-hydroxy-3-tert-butyl-aminopropoxy)-3'-methoxyphenyl]- 3-buten-2-one), derived from vanillin, were first investigated under in vivo and in vitro conditions. Vaninolol (0.1, 0.5, 1.0 mg/kg, i.v.), as well as propranolol, produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. These findings suggested that vaninolol possessed beta-adrenergic blocking activity, but was without alpha-adrenergic blocking activity. In isolated guinea-pig tissues, vaninolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that vaninolol was a beta-adrenoceptor competitive antagonist. The effect of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some beta 1-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol > vaninolol > propranolol. In addition, vaninolol had a mild direct cardiac depression at high concentrations and was without intrinsic sympathomimetic activity (ISA). Furthermore, binding characteristics of vaninolol and other beta-adrenoceptor antagonists were evaluated in [3H]dihydroalprenolol binding to guinea-pig ventricular membranes. The order of potency of beta-adrenoceptor antagonists in competing for the binding sites was (-)propranolol > vaninolol > or = atenolol. In conclusion, vaninolol was found to be a selective beta 1-adrenoceptor antagonist with relatively low lipophilicity in comparison with propranolol, devoid of ISA, and had a mild myocardial depressant effect.

  12. Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds.

    PubMed

    Avdieiev, Stanislav; Gera, Lajos; Havrylyuk, Dmytro; Hodges, Robert S; Lesyk, Roman; Ribrag, Vincent; Vassetzky, Yegor; Kavsan, Vadym

    2014-08-01

    Glioblastoma (GB), the most aggressive brain tumour, and mantle cell lymphoma (MCL), a rare but very aggressive type of lymphoma, are highly resistant to chemotherapy. GB and MCL chemotherapy gives very modest results, the vast majority of patients experience recurrent disease. To find out the new treatment modality for drug-resistant GB and MCL cells, combining of bradykinin (BK) antagonists with conventional temozolomide (TMZ) treatment, and screening of thiazolidinones derivatives were the main objectives of this work. As it was revealed here, BKM-570 was the lead compound among BK antagonists under investigation (IC50 was 3.3 μM) in human GB cells. It strongly suppressed extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation. BK antagonists did not decrease the viability of MCL cells, thus showing the cell-specific mode, while thiazolidinone derivatives, a novel group of promising anti-tumour compounds inhibited proliferation of MCL cells: IC₅₀ of ID 4526 and ID 4527 compounds were 0.27 μM and 0.16 μM, correspondingly. However, single agents are often not effective in clinic due to activation of collateral pathways in tumour cells. We demonstrated a strong synergistic effect after combinatorial treatment by BKM-570 together with TMZ that drastically increased cytotoxic action of this drug in rat and human glioma cells. Small proportion of cells was still viable after such treatment that could be explained by presence of TMZ-resistant cells in the population. It is possible to expect that the combined therapy aimed simultaneously at different elements of tumourigenesis will be more effective with lower drug concentrations than the first-line drug temozolomide used alone in clinics.

  13. Fancy bioisosteres: novel paracyclophane derivatives as super-affinity dopamine D3 receptor antagonists.

    PubMed

    Schlotter, Karin; Boeckler, Frank; Hübner, Harald; Gmeiner, Peter

    2006-06-15

    The exploration of the chemical diversity space depends on the discovery of novel bioisosteric elements. As a continuation of our project on bilayered arene surrogates, we herein report on [2.2]paracyclophane-derived dopamine D3 receptor antagonists of type 4 and 6. For the most promising test compound 6a, bearing a 2-methoxyphenyl substituent, a stereocontrolled preparation was performed when the planar chirality of enantiomers (R)-6a (FAUC 418) and (S)-6a caused a considerable differentiation of D3 binding, which is indicated by K(i) values of 0.19 and 3.0 nM, respectively. Functional experiments showed D3 antagonist properties for the paracyclophane derivatives of type 6. To elucidate putative bioactive low-energy conformations, DFT-based studies including the calculation of diagnostic magnetic shielding properties were performed. An 89% increase in volume for the [2.2]paracyclophane moiety compared to that of the monolayered benzofurane of lead compound 3b indicates higher plasticity of GPCR binding regions than usually expected.

  14. Stilbene derivatives as human 5-HT(6) receptor antagonists from the root of Caragana sinica.

    PubMed

    Kim, Dong Hyuk; Kim, Soon-Hee; Kim, Hyoung Ja; Jin, Changbae; Chung, Kwang Chul; Rhim, Hyewhon

    2010-01-01

    The 5-HT₆ receptor (5-HT₆R) is a member of the class of recently discovered 5-hydroxytryptamine (5-HT) receptors. Due to the lack of selective 5-HT₆R ligands, the cellular signaling mechanisms of the 5-HT₆R are poorly understood. We previously developed a cell-based high-throughput screening (HTS) method for the 5-HT₆R and screened synthetic chemical compounds. In the present study, we expanded our screening into natural products to find novel 5-HT₆R ligands. We found that the ethyl acetate fraction from the root of Caragana sinica (537-18BE) produced the most potent antagonistic activity. After further isolation of 537-18BE, we found that three stilbene derivatives, (+)-α-viniferin, miyabenol C and pallidol, are active constituents of 537-18BE inhibiting the 5-HT₆R. Among them, (+)-α-viniferin showed the most potent inhibition, and miyabenol C also produced a considerable inhibition. When examined effects on other neurotransmitters for selectivity, 537-18BE and three stilbene derivatives did not produce any notable effects on 5-HT₄, 5-HT₇, or muscarinic acetylcholine M1 (M(1)) receptors. Furthermore, 5-HT₆R antagonistic effects of (+)-α-viniferin, miyabenol C and pallidol were confirmed on extracellular signal-regulated kinase 1 and 2 (ERK1/2) which exerts effects in downstream pathways of 5-HT₆R activation.

  15. Piperazine-2,3-dicarboxylic acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors

    PubMed Central

    Irvine, Mark W.; Costa, Blaise M.; Dlaboga, Daniel; Culley, Georgia; Hulse, Richard; Scholefield, Caroline L.; Atlason, Palmi; Fang, Guangyu; Eaves, Richard; Morley, Richard; Mayo-Martin, Maria B.; Amici, Mascia; Bortolotto, Zuner A.; Donaldson, Lucy; Collingridge, Graham L.; Molnár, Elek; Monaghan, Daniel T.; Jane, David E.

    2011-01-01

    Competitive N-methyl-D-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N1-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype-selectivity among the more distantly related kainate receptor family. Compounds 18i and (−)-4 were the most potent kainate receptor antagonists and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/Kg i.p.) showed antinociceptive effects in an animal model of mild nerve injury. PMID:22111545

  16. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    PubMed

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  17. Synthesis and pharmacological evaluation of dimer derivatives of the bradykinin receptor antagonist HOE-140.

    PubMed

    Daffix, I; Amblard, M; Bergé, G; Dodey, P; Pruneau, D; Paquet, J L; Fouchet, C; Franck, R M; Defrêne, E; Luccarini, J M; Bélichard, P; Martinez, J

    1998-07-01

    The synthesis and pharmacological evaluation of dimer derivatives of the C-terminal fragments of the potent bradykinin antagonist HOE-140, linked through their N-termini, were performed. The influence of peptide moiety length was studied using the succinyl moiety as a linker. Our attention focused on the dimer of the C-terminal tetrapeptide of HOE-140 (compound JMV 980), which displayed some inhibiting activity (IC50 = 247 nM) for bradykinin B2 receptors. Unexpectedly, it was orally active in inhibiting bradykinin-induced hypotension in the rat. Based on this tetrapeptide dimer model, we synthesized pseudotetrapeptide dimer bradykinin antagonists 29 and 33, which exhibited high affinity (Ki = 76 and 61 nM, respectively) for the human cloned B2 receptor. In addition, compound 29 inhibited bradykinin-induced contraction of the human umbilical vein giving a pKB value of 6.45. Compounds 29 and 33 were selective toward B2 receptors because they did not bind to the cloned human B1 receptor up to 10 microM.

  18. Label-Free Kinetics: Exploiting Functional Hemi-Equilibrium to Derive Rate Constants for Muscarinic Receptor Antagonists.

    PubMed

    Riddy, Darren M; Valant, Celine; Rueda, Patricia; Charman, William N; Sexton, Patrick M; Summers, Roger J; Christopoulos, Arthur; Langmead, Christopher J

    2015-10-01

    Drug receptor kinetics is as a key component in drug discovery, development, and efficacy; however, determining kinetic parameters has historically required direct radiolabeling or competition with a labeled tracer. Here we present a simple approach to determining the kinetics of competitive antagonists of G protein-coupled receptors by exploiting the phenomenon of hemi-equilibrium, the state of partial re-equilibration of agonist, antagonist, and receptor in some functional assays. Using functional [Ca(2+)]i-flux and extracellular kinases 1 and 2 phosphorylation assays that have short incubation times and therefore are prone to hemi-equilibrium "behaviors," we investigated a wide range of structurally and physicochemically distinct muscarinic acetylcholine receptor antagonists. Using a combined operational and hemi-equilibrium model of antagonism to both simulate and analyze data, we derived estimates of association and dissociation rates for the test set of antagonists, identifying both rapidly dissociating (4-DAMP, himbacine) and slowly dissociating (tiotropium, glycopyrrolate) ligands. The results demonstrate the importance of assay incubation time and the degree of receptor reserve in applying the analytical model. There was an excellent correlation between estimates of antagonist pK(B), k(on), and k(off) from functional assays and those determined by competition kinetics using whole-cell [(3)H]N-methylscopolamine binding, validating this approach as a rapid and simple method to functionally profile receptor kinetics of competitive antagonists in the absence of a labeled tracer.

  19. Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies.

    PubMed

    Ceras, Javier; Cirauqui, Nuria; Pérez-Silanes, Silvia; Aldana, Ignacio; Monge, Antonio; Galiano, Silvia

    2012-06-01

    The combination of antagonism at histamine H(3) receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H(3) receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H(3) antagonism affinity. However, since all these derivatives failed to block K(ATP) channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H(3) antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.

  20. Sulfur-Containing 1,3-Dialkylxanthine Derivatives as Selective Antagonists at A1-Adenosine Receptors

    PubMed Central

    Kiriasis, Leonidas; Barone, Suzanne; Bradbury, Barton J.; Kammula, Udai; Campagne, Jean Michel; Secunda, Sherrie; Daly, John W.; Neumeyer, John L.; Pfleiderer, Wolfgang

    2012-01-01

    Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [[3H]-N6-(phenylisopropyl) adenosine as radioligand] or striatum [[3H]-5′-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was >740-fold A1 selective. PMID:2754711

  1. Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists.

    PubMed

    Lim, Chae Jo; Oh, Seung Ae; Lee, Byung Ho; Oh, Kwang-Seok; Yi, Kyu Yang

    2014-12-15

    The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.

  2. Discovery of histamine H3 receptor antagonistic property of simple imidazole-free derivatives: Preliminary pharmacological investigation.

    PubMed

    Barocelli, Elisabetta; Ballabeni, Vigilio; Manenti, Veronica; Flammini, Lisa; Bertoni, Simona; Morini, Giovanni; Comini, Mara; Impicciatore, Mariannina

    2006-03-01

    The histamine H3 receptor subtype negatively modulates the release of various neurotransmitters such as histamine, glutamate, norepinephrine, acetylcholine and many others mainly in the CNS and H3 antagonists have been developed to treat central diseases characterized by neurotransmission disturbance such as schizophrenia, memory/learning and sleep disorders. In search for non-imidazole histamine H3 receptor antagonists, currently indicated as a promising class of H3 blockers, a series of simple alkylpiperidine derivatives has been studied to attain a preliminary pharmacological profile. The compounds were characterized in vitro in terms of binding affinity, antagonistic potency and selectivity at rodent H3 receptors. The imidazole-free derivatives possessed moderate to pronounced antagonistic potency at guinea-pig ileal H3 receptor consistent with binding affinity at rat brain H3 receptors and showed a favourable receptor selectivity profile. For the compound 5, with the highest affinity at rat H3 receptors, comparable values were calculated in binding (pKi = 8.35) and functional (pA2 = 8.22) assays in SK-N-MC cells stably expressing human H3 receptors. These findings indicate to extend the investigation to pharmacokinetic property and central effects to gain deeper knowledge on the pharmacological potential of this compound.

  3. Synthesis and dual histamine H₁ and H₂ receptor antagonist activity of cyanoguanidine derivatives.

    PubMed

    Sadek, Bassem; Alisch, Rudi; Buschauer, Armin; Elz, Sigurd

    2013-11-15

    Premedication with a combination of histamine H₁ receptor (H₁R) and H₂ receptor (H₂R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H₁R and H₂R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H₁R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H₂R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H₂R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H₁R) and the isolated spontaneously beating right atrium (H₂R) of the guinea pig. The results indicate that, depending on the nature of the H₂R antagonist partial structure, the highest H₁R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H₁R, ileum) and 7.73 (H₂R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H₁R) and 6.61 (H₂R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H₁R and H₂R pharmacophoric moieties with mutually affinity-enhancing properties.

  4. Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

    PubMed Central

    Wu, Mingwei; Li, Yan; Fu, Xinmei; Wang, Jinghui; Zhang, Shuwei; Yang, Ling

    2014-01-01

    Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure–activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q2) = 0.509, non-cross-validated correlation coefficient (R2ncv) = 0.841 and the predicted correlation coefficient (R2pred) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents. PMID:25257526

  5. Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.

    PubMed

    Chen, Chen; Tucci, Fabio C; Jiang, Wanlong; Tran, Joe A; Fleck, Beth A; Hoare, Sam R; Wen, Jenny; Chen, Takung; Johns, Michael; Markison, Stacy; Foster, Alan C; Marinkovic, Dragan; Chen, Caroline W; Arellano, Melissa; Harman, John; Saunders, John; Bozigian, Haig; Marks, Daniel

    2008-05-15

    A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.

  6. Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists.

    PubMed

    Dastmalchi, Siavoush; Hamzeh-Mivehroud, Maryam; Ghafourian, Taravat; Hamzeiy, Hossain

    2008-01-01

    Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure-activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand-receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water-vacuum-water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand-receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists.

  7. Furoxan analogues of the histamine H3-receptor antagonist imoproxifan and related furazan derivatives.

    PubMed

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Cena, Clara; Sorba, Giovanni; Fruttero, Roberta; Gasco, Alberto

    2005-08-01

    Synthesis and pharmacological characterisation of a series of compounds in which the oxime substructure present in imoproxifan was constrained in the pentatomic NO-donor furoxan ring, as well as their structurally related furazan analogues devoid of NO-donating properties, are described. The whole series of products displayed reversible histamine H3-antagonistic activity on guinea-pig ileum. 4-(4-(3-(1H-Imidazol-4-yl)propoxy)phenyl)furoxan-3-carbonitrile 16 was also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of its H3-antagonistic properties. This phenomenon seems to be dependent on NO-mediated sGC activation. The lipophilic-hydrophilic balance of all the products was investigated.

  8. Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists.

    PubMed

    Zeng, Qingbei; Rosenblum, Stuart B; Yang, Zhaoxia; Jiang, Yueheng; McCormick, Kevin D; Aslanian, Robert G; Duguma, Luli; Kozlowski, Joseph A; Shih, Neng-Yang; Hey, John A; West, Robert E; Korfmacher, Walter A; Berlin, Michael; Boyce, Christopher W

    2013-11-01

    A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.

  9. A calixpyrrole derivative acts as an antagonist to GPER, a G-protein coupled receptor: mechanisms and models

    PubMed Central

    Lappano, Rosamaria; Rosano, Camillo; Pisano, Assunta; Santolla, Maria Francesca; De Francesco, Ernestina Marianna; De Marco, Paola; Dolce, Vincenza; Ponassi, Marco; Felli, Lamberto; Cafeo, Grazia; Kohnke, Franz Heinrich; Abonante, Sergio; Maggiolini, Marcello

    2015-01-01

    ABSTRACT Estrogens regulate numerous pathophysiological processes, mainly by binding to and activating estrogen receptor (ER)α and ERβ. Increasing amounts of evidence have recently demonstrated that G-protein coupled receptor 30 (GPR30; also known as GPER) is also involved in diverse biological responses to estrogens both in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds; nevertheless, some ligands exhibit opposed activity through these receptors. It is worth noting that, owing to the availability of selective agonists and antagonists of GPER for research, certain differential roles elicited by GPER compared with ER have been identified. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, such as breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data might open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives could be considered in future anticancer strategies targeting GPER in cancer cells. PMID:26183213

  10. A novel snake venom-derived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury

    PubMed Central

    Li, Ting-Ting; Fan, Man-Li; Hou, Shi-Xiang; Li, Xiao-Yi; Barry, Devin M; Jin, Hui; Luo, Sheng-Yong; Kong, Feng; Lau, Lit-Fui; Dai, Xiang-Rong; Zhang, Guo-Hui; Zhou, Lan-Lan

    2015-01-01

    Background and Purpose Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein (GP)Ib binding to von Willebrand factor (vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice. Experimental Approach Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). These mice were then treated with anfibatide (4, 2, 1 μg·kg−1), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/IIIα antagonist, was used as a positive control. Key Results Twenty-four hours after MCAO, anfibatide-treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbα, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice. Conclusions and Implications Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke. PMID:25917571

  11. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid.

    PubMed

    Borrelli, Francesca; Pagano, Ester; Romano, Barbara; Panzera, Stefania; Maiello, Francesco; Coppola, Diana; De Petrocellis, Luciano; Buono, Lorena; Orlando, Pierangelo; Izzo, Angelo A

    2014-12-01

    Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid (CB), which interacts with specific targets involved in carcinogenesis. Specifically, CBG potently blocks transient receptor potential (TRP) M8 (TRPM8), activates TRPA1, TRPV1 and TRPV2 channels, blocks 5-hydroxytryptamine receptor 1A (5-HT1A) receptors and inhibits the reuptake of endocannabinoids. Here, we investigated whether CBG protects against colon tumourigenesis. Cell growth was evaluated in colorectal cancer (CRC) cells using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and 3-amino-7-dimethylamino-2-methylphenazine hydrochloride assays; apoptosis was examined by histology and by assessing caspase 3/7 activity; reactive oxygen species (ROS) production by a fluorescent probe; CB receptors, TRP and CCAAT/enhancer-binding protein homologous protein (CHOP) messenger RNA (mRNA) expression were quantified by reverse transcription-polymerase chain reaction; small hairpin RNA-vector silencing of TRPM8 was performed by electroporation. The in vivo antineoplastic effect of CBG was assessed using mouse models of colon cancer. CRC cells expressed TRPM8, CB1, CB2, 5-HT1A receptors, TRPA1, TRPV1 and TRPV2 mRNA. CBG promoted apoptosis, stimulated ROS production, upregulated CHOP mRNA and reduced cell growth in CRC cells. CBG effect on cell growth was independent from TRPA1, TRPV1 and TRPV2 channels activation, was further increased by a CB2 receptor antagonist, and mimicked by other TRPM8 channel blockers but not by a 5-HT1A antagonist. Furthermore, the effect of CBG on cell growth and on CHOP mRNA expression was reduced in TRPM8 silenced cells. In vivo, CBG inhibited the growth of xenograft tumours as well as chemically induced colon carcinogenesis. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of CRC cells, an effect shared by other TRPM8 antagonists. CBG should be considered translationally in CRC prevention and cure.

  12. Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.

    PubMed

    Altimari, Jarrad M; Niranjan, Birunthi; Risbridger, Gail P; Schweiker, Stephanie S; Lohning, Anna E; Henderson, Luke C

    2014-11-01

    A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 μM and 29-151 μM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken.

  13. Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists

    PubMed Central

    Fan, Jiabing; Im, Choong Sung; Guo, Mian; Cui, Zhong-Kai; Fartash, Armita; Kim, Soyon; Patel, Nikhil; Bezouglaia, Olga; Wu, Benjamin M.; Wang, Cun-Yu

    2016-01-01

    Although adipose-derived stem cells (ASCs) are an attractive cell source for bone tissue engineering, direct use of ASCs alone has had limited success in the treatment of large bone defects. Although bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors to promote osteogenic differentiation of ASCs, their clinical applications require supraphysiological dosage, leading to high medical burden and adverse side effects. In the present study, we demonstrated an alternative approach that can effectively complement the BMP activity to maximize the osteogenesis of ASCs without exogenous application of BMPs by regulating levels of antagonists and agonists to BMP signaling. Treatment of ASCs with the amiloride derivative phenamil, a positive regulator of BMP signaling, combined with gene manipulation to suppress the BMP antagonist noggin, significantly enhanced osteogenic differentiation of ASCs through increased BMP–Smad signaling in vitro. Furthermore, the combination approach of noggin suppression and phenamil stimulation enhanced the BMP signaling and bone repair in a mouse calvarial defect model by adding noggin knockdown ASCs to apatite-coated poly(lactic-coglycolic acid) scaffolds loaded with phenamil. These results suggest novel complementary osteoinductive strategies that could maximize activity of the BMP pathway in ASC bone repair while reducing potential adverse effects of current BMP-based therapeutics. Significance Although stem cell-based tissue engineering strategy offers a promising alternative to repair damaged bone, direct use of stem cells alone is not adequate for challenging healing environments such as in large bone defects. This study demonstrates a novel strategy to maximize bone formation pathways in osteogenic differentiation of mesenchymal stem cells and functional bone formation by combining gene manipulation with a small molecule activator toward osteogenesis. The findings indicate promising stem cell

  14. Multivalent benzene polyphosphate derivatives are non-Ca(2+)-mobilizing Ins(1,4,5)P3 receptor antagonists.

    PubMed

    Mills, Stephen J; Luyten, Tomas; Erneux, Christophe; Parys, Jan B; Potter, Barry V L

    2012-12-01

    Inositol 1,4,5-trisphosphate [Ins(1,4,5)P31] mobilizes intracellular Ca(2+) through the Ins(1,4,5)P3 receptor [InsP3R]. Although some progress has been made in the design of synthetic InsP3R partial agonists and antagonists, there are still few examples of useful small molecule competitive antagonists. A "multivalent" approach is explored and new dimeric polyphosphorylated aromatic derivatives were designed, synthesized and biologically evaluated. The established weak InsP3R ligand benzene 1,2,4-trisphosphate [Bz(1,2,4)P32] is dimerized through its 5-position in two different ways, first directly as the biphenyl derivative biphenyl 2,2',4,4',5,5'-hexakisphosphate, [BiPh(2,2',4,4',5,5')P68] and with its regioisomeric biphenyl 3,3',4,4',5,5'-hexakisphosphate [BiPh(3,3',4,4',5,5')P611]. Secondly, a linker motif is introduced in a flexible ethylene-bridged dimer (9) with its corresponding 1,2-bisphosphate dimer (10), both loosely analogous to the very weak antagonist 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA 7). In permeabilized L15 fibroblasts overexpressing type 1 InsP3R, BiPh(2,2',4,4',5,5')P6 (8) inhibits Ins(1,4,5)P3-induced Ca(2+) release in a apparently competitive fashion [IC50 187 nM] and the Bz(1,2,4)P3 dimer (9) is only slightly weaker [IC50 380 nM]. Compounds were also evaluated against type I Ins(1,4,5)P3 5-phosphatase. All compounds are resistant to dephosphorylation, with BiPh(2,2',4,4',5,5')P6 (8), being the most effective inhibitor of any biphenyl derivative synthesized to date [IC50 480 nM] and the Bz(1,2,4)P3 ethylene dimer (9) weaker [IC50 3.55 μM]. BiPh(3,3',4,4',5,5')P6 (11) also inhibits 5-phosphatase [IC50 730 nM] and exhibits unexpected Ca(2+) releasing activity [EC50 800 nM]. Thus, relocation of only a single mirrored phenyl phosphate group in (11) from that of antagonist (8) does not markedly change enzyme inhibitory activity, but elicits a dramatic switch in Ca(2+)-releasing activity. Such new agents demonstrate the

  15. Cationic derivatives of dextran and hydroxypropylcellulose as novel potential heparin antagonists.

    PubMed

    Kamiński, Kamil; Płonka, Monika; Ciejka, Justyna; Szczubiałka, Krzysztof; Nowakowska, Maria; Lorkowska, Barbara; Korbut, Ryszard; Lach, Radosław

    2011-10-13

    Cationic derivatives of dextran (Dex) and hydroxypropylcellulose (HPC) were studied as potential alternatives of protamine sulfate (PS) used in the reversal of anticoagulant activity of heparin. The modification was performed by the attachment of cationic groups to the Dex main chain or by grafting short side chains of a polycation onto HPC. The cationic derivatives of these polysaccharides were found to bind heparin with the efficiency increasing with growing degree of cationic modification. The degree of cationic modification and consequently the ζ potential of the polymers do not have to be high to achieve effective heparin binding. The size of the complexes of cationic Dex with unfractionated heparin (UFH) is a few micrometers. For complexes of cationic HPC and UFH the size is much below 1 μm, both below and above the lower critical solution temperature of HPC. None of the cationic polysaccharides studied caused hemolysis. The concentrations of the polymers inducing the aggregation of human erythrocytes in vitro were determined.

  16. Benzamide derivatives and their constrained analogs as histamine H3 receptor antagonists.

    PubMed

    Nirogi, Ramakrishna; Shinde, Anil; Tiriveedhi, Vinaykumar; Kota, Laxman; Saraf, Sangram Keshari; Badange, Rajesh Kumar; Mohammed, Abdul Rasheed; Subramanian, Ramkumar; Muddana, Nageshwararao; Bhyrapuneni, Gopinadh; Abraham, Renny

    2016-01-27

    A series of 4-(1-substituted piperidin-4-yloxy) benzamides and 6-(1-substituted piperidin-4-yloxy)-3,4-dihydro-2H-isoquinolin-1-one derivatives have been synthesized and tested for their binding affinity towards H3 receptor. Most of these synthesized compounds have displayed potent binding affinity for H3 receptor when tested in in vitro binding assay. Preliminary SAR studies, functional activity, pharmacokinetic profile and efficacy profile constitute the subject matter of this communication.

  17. Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers.

    PubMed

    Tang, Li; Zhao, Liying; Hong, Lingjuan; Yang, Fenyan; Sheng, Rong; Chen, Jianzhong; Shi, Ying; Zhou, Naimin; Hu, Yongzhou

    2013-10-01

    A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.

  18. Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant

    PubMed Central

    Zakaria, Z; Tivnan, A; Flanagan, L; Murray, D W; Salvucci, M; Stringer, B W; Day, B W; Boyd, A W; Kögel, D; Rehm, M; O'Brien, D F; Byrne, A T; Prehn, J H M

    2016-01-01

    Background: Resistance to temozolomide (TMZ) greatly limits chemotherapeutic effectiveness in glioblastoma (GBM). Here we analysed the ability of the Inhibitor-of-apoptosis-protein (IAP) antagonist birinapant to enhance treatment responses to TMZ in both commercially available and patient-derived GBM cells. Methods: Responses to TMZ and birinapant were analysed in a panel of commercial and patient-derived GBM cell lines using colorimetric viability assays, flow cytometry, morphological analysis and protein expression profiling of pro- and antiapoptotic proteins. Responses in vivo were analysed in an orthotopic xenograft GBM model. Results: Single-agent treatment experiments categorised GBM cells into TMZ-sensitive cells, birinapant-sensitive cells, and cells that were insensitive to either treatment. Combination treatment allowed sensitisation to therapy in only a subset of resistant GBM cells. Cell death analysis identified three principal response patterns: Type A cells that readily activated caspase-8 and cell death in response to TMZ while addition of birinapant further sensitised the cells to TMZ-induced cell death; Type B cells that readily activated caspase-8 and cell death in response to birinapant but did not show further sensitisation with TMZ; and Type C cells that showed no significant cell death or moderately enhanced cell death in the combined treatment paradigm. Furthermore, in vivo, a Type C patient-derived cell line that was TMZ-insensitive in vitro and showed a strong sensitivity to TMZ and TMZ plus birinapant treatments. Conclusions: Our results demonstrate remarkable differences in responses of patient-derived GBM cells to birinapant single and combination treatments, and suggest that therapeutic responses in vivo may be greatly affected by the tumour microenvironment. PMID:26657652

  19. Antagonist Targeting microRNA-155 Protects against Lithium-Pilocarpine-Induced Status Epilepticus in C57BL/6 Mice by Activating Brain-Derived Neurotrophic Factor

    PubMed Central

    Cai, Zhengxu; Li, Song; Li, Sheng; Song, Fan; Zhang, Zhen; Qi, Guanhua; Li, Tianbai; Qiu, Juanjuan; Wan, Jiajia; Sui, Hua; Guo, Huishu

    2016-01-01

    Epilepsy is a severe brain disorder affecting numerous patients. Recently, it is inferred that modulation of microRNA-155 (miR-155) could serve as a promising treatment of mesial temporal lobe epilepsy. In the current study, the therapeutic potential of miR-155 antagonist against temporal lobe epilepsy (TLE) was evaluated and the underlying mechanism involved in this regulation was explored. TLE model was induced by lithium-pilocarpine method. The effect of miR-155 antagonist on epilepticus symptoms of TLE mice was assessed using Racine classification and electroencephalogram (EEG) recordings. The expression of brain-derived neurotrophic factor (BDNF) and its association with miR-155 were also assessed with a series of experiments. Our results showed that level of miR-155 was significantly up-regulated after induction of TLE model. Based on the results of EEG and behavior analyses, seizures in mice were alleviated by miR-155 antagonist. Moreover, administration of miR-155 antagonist also significantly increased the level of BDNF. The results of dual luciferase assay and Western blotting showed that miR-155 antagonist exerted its action on status epilepticus by directly regulating the activity of BDNF. Taken all the information together, our results demonstrated that miR-155 antagonist might firstly induce the expression of BDNF, which then contributed to the alleviation of epilepsy in the current study. PMID:27303295

  20. Synthesis, crystal structure, biological evaluation, and molecular docking studies of quinoline-arylpiperazine derivative as potent α1A-adrenoceptor antagonist

    NASA Astrophysics Data System (ADS)

    Xu, Wei; Jiang, Renwang; Yuan, Mu

    2017-02-01

    Arylpiperazine derivatives received special attention owing to their antagonist potency on α1-adrenoceptors (α1-ARs). In this work, quinoline-arylpiperazine derivative (1) was synthesized and its structural properties were investigated using single crystal X-ray diffraction analysis and theoretical calculations. Biological evaluation in vitro revealed that compound 1 exhibited a 3-fold higher selectivity for α1A-AR over than α1B subtype when compared to non-selective antagonist prazosin. Molecular docking studies shed light on the antagonistic activity of both 1 and prazosin on α1A and α1B-AR. The docking results suggested that residues Gln177, Phe86, Phe288, Phe308, Phe312 and Tyr316 were identified as the major sites for the two agents binding to the α1A receptor. As depicted by pharmacophoric model, 1 was deemed to be the α1A-selective antagonist on the basis of pharmacophoric features. Our present work may provide valuable information for better drug design of subtype-selective α1-AR antagonists.

  1. Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T.

    PubMed

    Malmberg, Annika B; Gilbert, Heather; McCabe, R Tyler; Basbaum, Allan I

    2003-01-01

    Subunit non-selective N-methyl-D-aspartate (NMDA) receptor antagonists reduce injury-induced pain behavior, but generally produce unacceptable side effects. In this study, we examined the antinociceptive and motor effects of cone snail venom-derived peptides, conantokins G and T (conG and conT), which are selective inhibitors of the NR2B or NR2A and NR2B subtypes of the NMDA receptor, respectively. We tested the effects of conG and conT in models of tissue (formalin test), nerve injury (partial sciatic nerve ligation) and inflammation-induced (intraplantar Complete Freund's Adjuvant; CFA) pain in mice. In the formalin test, intrathecal (i.t.) conG or conT suppressed the ongoing pain behavior (ED(50) and 95% confidence intervals (CI), 11 (7-19) and 19 (11-33), respectively) at doses that were 17-27 times lower than those required to impair motor function (accelerating rotarod treadmill test: ED(50) and 95% CI, 300 (120-730) and 320 (190-540) pmol, respectively). By comparison, SNX-111, an N-type voltage-sensitive calcium channel antagonist that is also derived from cone snail venom, produced significant motor impairment at a dose (3.0 pmol, i.t.) that was only partially efficacious in the formalin test. Furthermore, conG reversed the allodynia produced by nerve injury, with greater potency on thermal (ED50 and 95% CI, 24 (10-55) pmol) than on mechanical allodynia (59 (33-105) pmol). Finally, a single dose of conG (100 pmol, i.t.) also reduced CFA-evoked thermal and mechanical allodynia. Taken together, these results demonstrate that conantokins exhibit potent antinociceptive effects in several models of injury-induced pain. The study supports the notion that drugs directed against subtypes of the NMDA receptor, by virtue of their reduced side-effect profile, hold promise as novel therapeutic agents for the control of pain.

  2. Effects of structural modifications of N-CPM-normorphine derivatives on agonist and antagonist activities in isolated organs.

    PubMed

    Riba, P; Tóth, Z; Hosztafi, S; Friedmann, T; Fürst, S

    2003-01-01

    The agonistic and antagonistic properties of N-cyclopropylmethyl (N-CPM) morphine derivatives were observed in mouse vas deferens (MVD), longitudinal muscle of guinea pig ileum (GPI) and rabbit vas deferens (LVD). In MVD the K(e) values of the titled compounds (N-CPM-morphine, N-CPM-isomorphine, N-CPM-dihydromorphine, N-CPM-dihydroisomorpPhine, N-CPM-dihydromorphone and naltrexone) were measured for mu-, kappa- and delta-receptors using normorphine, ethylketocyclazocine (EKC) and D-Pen2-D-Pen5-enkephaline (DPDPE) as selective agonists on the receptors, respectively. For mu-receptors of MVD the tested compounds showed similar affinity. For kappa-receptors the non-iso-6-OH derivatives possessed much less affinity than the iso-derivatives. Similar difference could be observed for delta-receptors. The agonistic activities of these compounds in MVD were observed to be between 0-20% of the inhibition of muscle contractions. In GPI the compounds except naltrexone possessed strong agonistic activities effectively antagonized by nor-binaltorphimine (nor-BNI) (K(e) of nor-BNI was 0.23 nM) suggesting that they were strong kappa-receptor agonists. We investigated these agents in LVD too, which contains kappa-receptors, but they did not produce any agonist potencies. It raises the possibility that the kappa-receptor subtypes of LVD and MVD are different from the kappa-receptor subtype of GPI or the vasa deferentia contain much fewer kappa-receptors than GPI and the intrinsic activities of these compounds are too small to reach the 50% inhibition of the contractions.

  3. Concentration-dependent antagonistic persuasion of SDS and naphthalene derivatives on the fibrillation of stem bromelain.

    PubMed

    Qadeer, Atiyatul; Ahmad, Ejaz; Zaman, Masihuz; Khan, Mohd Wasif; Khan, Javed Masood; Rabbani, Gulam; Tarique, Khaja Faisal; Sharma, Gaurav; Gourinath, Samudrala; Nadeem, Sajid; Badr, Gamal; Khan, Rizwan Hasan

    2013-12-01

    Sodium dodecyl sulfate, a biological membrane mimetic, can be used to study the conversion of globular proteins into amyloid fibrils in vitro. Using multiple approaches, the effect of SDS was examined on stem bromelain (SB), a widely recognized therapeutic protein. SB is known to exist as a partially folded intermediate at pH 2.0, situation also encountered in the gastrointestinal tract (its site of absorption). In the presence of sub-micellar SDS concentration (500-1000 μM), this intermediate was found to exhibit great propensity to form large-sized β-sheeted aggregates with fibrillar morphology, the hall marks of amyloid structure. We also observed inhibition of fibrillation by two naphthalene-based compounds, ANS and bis-ANS. While bis-ANS significantly inhibited fibril formation at 50 μM, ANS did so at relatively higher concentration (400 μM). Alcohols, but not salts, were found to weaken the inhibitory action of these compounds suggesting the possible involvement of hydrophobic interactions in their binding to protein. Besides, isothermal titration calorimetry and molecular docking studies suggested that inhibition of fibrillation by these naphthalene derivatives is mediated not just through hydrophobic forces, but also by disruption of π-π interactions between the aromatic residues together with the inter-polypeptide chain repulsion among negatively charged ANS/bis-ANS bound SB.

  4. Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist.

    PubMed

    Hwang, Tsong-Long; Hung, Chih-Hao; Hsu, Ching-Yun; Huang, Yin-Ting; Tsai, Yu-Chi; Hsieh, Pei-Wen

    2013-06-14

    Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2˙(-)) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein.

  5. Crystal structures of four indole derivatives as possible cannabinoid allosteric antagonists

    PubMed Central

    Kerr, Jamie R.; Trembleau, Laurent; Storey, John M. D.; Wardell, James L.; Harrison, William T. A.

    2015-01-01

    The crystal structures of four indole derivatives with various substituents at the 2-, 3- and 5-positions of the ring system are described, namely, ethyl 3-(5-chloro-2-phenyl-1H-indol-3-yl)-3-phenyl­propano­ate, C25H22ClNO2, (I), 2-bromo-3-(2-nitro-1-phenyl­eth­yl)-1H-indole, C16H13BrN2O2, (II), 5-meth­oxy-3-(2-nitro-1-phenyl­eth­yl)-2-phenyl-1H-indole, C23H20N2O3, (III), and 5-chloro-3-(2-nitro-1-phenyl­eth­yl)-2-phenyl-1H-indole, C22H17ClN2O2, (IV). The dominant inter­molecular inter­action in each case is an N—H⋯O hydrogen bond, which generates either chains or inversion dimers. Weak C—H⋯O, C—H⋯π and π–π inter­actions occur in these structures but there is no consistent pattern amongst them. Two of these compounds act as modest enhancers of CB1 cannabanoid signalling and two are inactive. PMID:26090143

  6. Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.

    PubMed

    Li, Guo; Aschenbach, Lindsey C; Chen, Jianyang; Cassidy, Michael P; Stevens, David L; Gabra, Bichoy H; Selley, Dana E; Dewey, William L; Westkaemper, Richard B; Zhang, Yan

    2009-03-12

    Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible mu opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K(i) = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the delta receptor (DOR) and more than 150-fold selectivity over the kappa receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.

  7. Synthesis, QSAR and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing 1-methyl-4,5-dichloroimidazolyl substituents.

    PubMed

    Hosseini, Maryam; Miri, Ramin; Amini, Mohsen; Mirkhani, Hossein; Hemmateenejad, Bahram; Ghodsi, Shahram; Alipour, Eskandar; Shafiee, Abbas

    2007-10-01

    A group of dialkyl and diarylester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 was replaced by a 1-methyl-4,5-dichloroimidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K(+)concentration of guinea-pig ileum longitudinal smooth muscle. The structure of all compounds was confirmed by IR,(1)H-NMR, and mass spectra. The calcium-channel antagonist activity of compounds 10a-f demonstrated that compound 10b was the most active and 10f the least active one. With unsymmetrical diesters 12a-k, the most active compound was the ethyl, phenethyl derivative. Structural parameters on the calcium-channel antagonist activity were evaluated by QSAR analysis and a linear correlation was found between the -log IC(50) values of these compounds and their constitutional and topological properties.

  8. Exploring details about structure requirements based on novel CGRP receptor antagonists urethanamide, aspartate, succinate and pyridine derivatives by in silico methods

    NASA Astrophysics Data System (ADS)

    Li, Yan; He, Haoran; Wang, Jinghui; Han, Chunxiao; Feng, Jiaqi; Zhang, Shuwei; Yang, Ling

    2014-09-01

    The migraine never fails to afflict individuals in the world that knows no lack of such cases. CGRP (calcitonin gene-related peptide) is found closely related to migraine and olcegepant (BIBN4096) is effective in alleviating the pain. In our work, the combination of ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies along with molecular docking was applied to provide us insights about how urethanamide, pyridine and aspartate and succinate derivatives (novel CGRP receptor antagonists) play a part in inhibiting the activity of CGRP receptor. The optimal CoMSIA model shows the Q2 of 0.505, R2ncv of 0.992 and its accurate predictive ability was confirmed by checking out an independent test set which gave R2pred value of 0.885. Besides, the 3D contour maps help us identify how different groups affect the antagonist activity while connecting to some key positions. In addition, the docking analysis shows the binding site emerging as the distorted “V” shape and including two binding pockets: one of them is hydrophobic, fixing the structural part 3 of compound 80, the other anchors the part 1 of compound 80. The docking analysis also shows the interaction mechanism between compound 80 and CGRP receptor, similar to the interaction between olcegepant and CGRP receptor. The findings derived from this work reveal the mechanism of related antagonists and facilitate the future rational design of novel antagonists with higher potency.

  9. Glycogen phosphorylase a inhibitors with a phenethylphenylphthalimide skeleton derived from thalidomide-related alpha-glucosidase inhibitors and liver X receptor antagonists.

    PubMed

    Motoshima, Kazunori; Ishikawa, Minoru; Sugita, Kazuyuki; Hashimoto, Yuichi

    2009-09-01

    Novel glycogen phosphorylase a (GPa) inhibitors with a phenethylphenylphthalimide skeleton were prepared based on alpha-glucosidase inhibitors and liver X receptor (LXR) antagonists derived from thalidomide. Their structure-activity relationships were analyzed. Some of the compounds thus prepared showed potent inhibitory activity against rabbit muscle GPa with more than 10-fold greater efficacy than a typical GPa inhibitor, 1,4-dideoxy-1,4-imino-D-arabinitol.

  10. Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives.

    PubMed

    Abreu, Paula A; Castro, Helena C; Paes-de-Carvalho, Roberto; Rodrigues, Carlos R; Giongo, Viveca; Paixão, Izabel C N P; Santana, Marcos V; Ferreira, Jainne M; Caversan, Octavia M; Leão, Raquel A C; Marins, Luana M S; Henriques, André M; Farias, Florence M C; Albuquerque, Magaly G; Pinheiro, Sergio

    2013-02-01

    Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R(2) = 0.836), presented a satisfactory internal predictive ability (Q(2) = 0.609) and contained the descriptors (E(HOMO), Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-D-aspartic acid receptor antagonists.

  11. Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives

    PubMed Central

    Bahashwan, Saleh A.; Fayed, Ahmed A.; Ramadan, Mohamed A.; Amr, Abd El-Galil E.; Al-Harbi, Naif O.

    2014-01-01

    A series of substituted pyrazole, triazole and thiazole derivatives (2–13) were synthesized from 1-(naphtho[1,2-d]thiazol-2-yl)hydrazine as starting material and evaluated as androgen receptor antagonists and anti-prostate cancer agents. The newly synthesized compounds showed potent androgen receptor antagonists and anti-prostate cancer activities with low toxicity (lethal dose 50 (LD50)) comparable to Bicalutamide as reference drug. The structures of newly synthesized compounds were confirmed by IR, 1H-NMR, 13C-NMR, and MS spectral data and elemental analysis. The detailed synthesis, spectroscopic data, LD50 values and pharmacological activities of the synthesized compounds are reported. PMID:25421248

  12. Quinazolin-4-one derivatives: A novel class of non-competitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists

    PubMed Central

    Mosley, Cara A.; Acker, Timothy M.; Hansen, Kasper B.; Mullasseril, Praseeda; Andersen, Karen T.; Le, Phuong; Vellano, Kimberly M.; Bräuner-Osborne, Hans; Liotta, Dennis C.; Traynelis, Stephen F.

    2010-01-01

    We describe a new class of subunit-selective antagonists of N-methyl D-Aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is non-competitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), a non-competitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of non-competitive subunit-selective NMDA receptor antagonists. PMID:20684595

  13. Synthesis of sterically encumbered 11β-aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists.

    PubMed

    Pandya, Keyur; Dietrich, David; Seibert, Julia; Vederas, John C; Odermatt, Alex

    2013-11-01

    11β-Hydroxyprogesterone is a well-known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2. It also activates the mineralocorticoid receptor (MR). Modulation of corticosteroid action by inhibition of 11βHSDs or blocking MR is currently under consideration for treatment of electrolyte disturbances, metabolic diseases and chronic inflammatory disorders. We established conditions to synthesize sterically demanding 11β-aminoprogesterone, which following subsequent nucleophilic or reductive amination, allowed extension of the amino group to prepare amino acid derivatives. Biological testing revealed that some of the 11β-aminoprogesterone derivatives selectively inhibit 11βHSD2. Moreover, two compounds that did not significantly inhibit 11βHSDs had antagonist properties on MR. The 11β-aminoprogesterone derivatives form a basis for the further development of improved modulators of corticosteroid action.

  14. Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists

    PubMed Central

    2016-01-01

    UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models. PMID:27331270

  15. Quantitative structure-activity relationships (QSAR) of some 2,2-diphenyl propionate (DPP) derivatives of muscarinic antagonists

    SciTech Connect

    Gordon, R.K.; Breuer, E.; Padilla, F.N.; Chiang, P.K.

    1987-05-01

    QSAR between biological activities and molecular-chemical properties were investigated to aid in designing more effective and potent antimuscarinic pharmacophores. A molecular modeling program was used to calculate geometrical and topological values of a series of DPP pharmacophores. The newly synthesized pharmacophores were tested for their antagonist activities by: (1) inhibition of (N-methyl-/sup 3/H)scopolamine binding assay to the muscarinic receptors of N4TG1 neuroblastoma cells; (2) blocking of acetylcholine-induced contraction of guinea pig ileum; and (3) inhibition of carbachol-induced ..cap alpha..-amylase release from rat pancreas. The differences in the log of these biological activities were directly and significantly related to the distances between the carbonyl oxygen of the DPP and the quaternary nitrogen of the modified pharmacophores. The biological activities, while depending on each particular assay, varied between three and four logs of activity. The charge remained the same in all the pharmacophores. There were no QSAR correlations between molecular volume, molecular connectivity, or principle moments and their antagonistic activities, although multivariate QSAR was not employed. Thus, based on distance geometry, potent muscarinic pharmacophores can be predicted.

  16. Identification of opioid ligands possessing mixed micro agonist/delta antagonist activity among pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone [correction of hydropmorphone].

    PubMed

    Ananthan, Subramaniam; Khare, Naveen K; Saini, Surendra K; Seitz, Lainne E; Bartlett, Jeffrey L; Davis, Peg; Dersch, Christina M; Porreca, Frank; Rothman, Richard B; Bilsky, Edward J

    2004-03-11

    A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid delta, micro, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [(35)S]GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the micro and delta receptors. Their affinities at the kappa site were nearly 10-fold less than their binding affinities at the micro and delta sites. Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the micro site. Nearly all of the ligands possessing an N-methyl group at the17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the micro receptor with varying potencies and efficacies. In the [(35)S]GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors. In antinociceptive evaluations using the warm-water tail-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route. Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed micro agonist/delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard micro agonist morphine produces significant tolerance, repeated administration of the micro agonist/delta antagonist

  17. Effects of histamine and its antagonists on murine T-cells and bone marrow-derived dendritic cells.

    PubMed

    Hu, Xiufen; Zafar, Mohammad Ishraq; Gao, Feng

    2015-01-01

    We determined the effects of histamine and its antagonists on the surface marker expression of dendritic cells (DCs) and the influence of lipopolysaccharide (LPS), histamine, and histamine receptor antagonists on DCs and T-cells. The bone marrow was extracted from the femurs and tibiae of 6- to 8-week-old female Balb/c mice and cultured in medium containing penicillin, streptomycin, L-glutamine, fetal calf serum, or granulocyte macrophage colony-stimulating factor (GM-CSF) alone or with interleukin (IL)-4. The cells received three different doses of LPS and histamine, plus three different doses of descarboethoxyloratadine (DCL). We assayed the supernatant for various cytokines. The spleen cells of DO11.10 mice were examined by flow cytometry, which included labeling and sorting CD4+ T-cells, as well as coculture of DCs and T-cells with ovalbumin (OVA)323-339 peptide. Histamine or histamine plus DCL did not affect the expression of major histocompatibility complex class II, CD11c, CD11b, CD86, and CD80. However, GM-CSF increased the expression of all markers except CD80. Histamine increased interferon-γ production in GM-CSF + IL-4-cultured cells; it also enhanced IL-10 production, but suppressed IL-12 production in LPS-stimulated DCs with no DCL. Cimetidine inhibited IL-10 production and restored IL-12 secretion in LPS-treated DCs. LPS increased IL-10 and decreased IL-12 levels. GM-CSF + IL-4-generated DCs had a stronger stimulatory effect on DO11.10 T-cell proliferation than GM-CSF-generated DCs. Inducible costimulator ligand expression was higher in GM-CSF + IL-4- than in GM-CSF-generated DC groups after 2 days of coculture, but decreased 4 days later. IL-13 production was higher in bone marrow DCs generated with GM-CSF than in those generated with GM-CSF + IL-4. OVA-pulsed DCs and OVA-plus-DCL DCs showed increased IL-12 levels. OVA plus LPS increased both IL-10 and interferon-α. Although histamine or histamine receptor-1 antagonists did not influence DC LPS

  18. In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors

    SciTech Connect

    Molina-Molina, José-Manuel; Amaya, Esperanza; Grimaldi, Marina; Sáenz, José-María; Real, Macarena; Fernández, Mariana F.; Balaguer, Patrick; Olea, Nicolás

    2013-10-01

    Bisphenols are a group of chemicals structurally similar to bisphenol-A (BPA) in current use as the primary raw material in the production of polycarbonate and epoxy resins. Some bisphenols are intended to replace BPA in several industrial applications. This is the case of bisphenol-S (BPS), which has an excellent stability at high temperature and resistance to sunlight. Studies on the endocrine properties of BPS have focused on its interaction with human estrogen receptor alpha (hERα), but information on its interaction with other nuclear receptors is scarce. The aim of this study was to investigate interactions of BPS, BPF, BPA and its halogenated derivatives, tetrachlorobisphenol A (TCBPA), and tetrabromobisphenol A (TBBPA), with human estrogen receptors (hERα and hERβ), androgen receptor (hAR), and pregnane X receptor (hPXR), using a panel of in vitro bioassays based on competitive binding to nuclear receptors (NRs), reporter gene expression, and cell proliferation assessment. BPS, BPF, and BPA efficiently activated both ERs, while TCBPA behaved as weak hERα agonist. Unlike BPF and BPA, BPS was more active in the hERβ versus hERα assay. BPF and BPA were full hAR antagonists (BPA > BPF), whereas BPA and BPS were weak hAR agonists. Only BPA, TCBPA, and TBBPA, were hPXR agonists (TCBPA > TBBPA > BPA). These findings provide evidence that BPA congeners and derivatives disrupt multiple NRs and may therefore interfere with the endocrine system. Hence, further research is needed to evaluate the potential endocrine-disrupting activity of putative BPA substitutes. - Highlights: • We investigated the agonist/antagonist activities of BPS, BPF, BPA, TCBPA and TBBPA. • The direct interaction of these compounds with hERα, hERβ, hAR and hPXR was studied. • BPA congeners and derivatives were found to disrupt multiple NRs. • Further evaluation of their role as endocrine-disrupting chemicals is needed.

  19. Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

    PubMed

    Kiris, Erkan; Nuss, Jonathan E; Stanford, Stephanie M; Wanner, Laura M; Cazares, Lisa; Maestre, Michael F; Du, Hao T; Gomba, Glenn Y; Burnett, James C; Gussio, Rick; Bottini, Nunzio; Panchal, Rekha G; Kane, Christopher D; Tessarollo, Lino; Bavari, Sina

    2015-01-01

    There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.

  20. Synthesis of a potent and selective (18)F-labeled delta-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging.

    PubMed

    Ryu, Eun Kyoung; Wu, Zhanhong; Chen, Kai; Lazarus, Lawrence H; Marczak, Ewa D; Sasaki, Yusuke; Ambo, Akihiro; Salvadori, Severo; Ren, Chuancheng; Zhao, Heng; Balboni, Gianfranco; Chen, Xiaoyuan

    2008-03-27

    Identification and pharmacological characterization of two new selective delta-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high delta selectivity, H-Dmt-Tic--Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of (18)F-labeled compounds prepared by the coupling of N-succinimidyl 4-[ (18)F]fluorobenzoate ([(18)F]SFB) with Boc-Dmt-Tic--Lys(Z)-OH under slightly basic conditions at 37 degrees C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [(18)F]- 1 was about 25-30% ( n = 5) starting from [(18)F]SFB ( n = 5) with an effective specific activity about 46 GBq/micromol. In vitro autoradiography studies showed prominent uptake of [ (18)F]- 1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective delta-opioid receptor antagonist), suggesting high specific binding of [(18)F]- 1 to delta-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [(18)F]- 1 in rat brain, since it fails to cross the blood-brain barrier. This study demonstrates the suitability of [ (18)F]- 1 for imaging peripheral delta-opioid receptors.

  1. 6β-N-heterocyclic substituted naltrexamine derivative NAP as a potential lead to develop peripheral mu opioid receptor selective antagonists.

    PubMed

    Yuan, Yunyun; Stevens, David L; Braithwaite, Amanda; Scoggins, Krista L; Bilsky, Edward J; Akbarali, Hamid I; Dewey, William L; Zhang, Yan

    2012-07-15

    A 6β-N-heterocyclic substituted naltrexamine derivative, NAP, was proposed as a peripheral mu opioid receptor (MOR) selective antagonist based on the in vitro and in vivo pharmacological and pharmacokinetic studies. To further validate this notion, several functional assays were carried out to fully characterize this compound. In the charcoal gavage and intestinal motility assay in morphine-pelleted mice, when administered 0.3 mg/kg or higher doses up to 3 mg/kg subcutaneously, NAP significantly increased the intestinal motility compared to the saline treatment. The comparative opioid withdrawal precipitation study and the lower locomotor assay demonstrated that NAP showed only marginal intrinsic effect in the central nervous system either given subcutaneously or intravenously: no jumps were witnessed for the tested animals even given up to a dose of 50 mg/kg, while similar noticeable wet-dog shakes only occurred at the dose 50 times of those for naloxone or naltrexone, and significant reduction of the hyper-locomotion only happened at the dose as high as 32 mg/kg. Collectively, these results suggested that NAP may serve as a novel lead to develop peripheral MOR selective antagonist which might possess therapeutic potential for opioid-induced bowel dysfunction (OBD), such as opioid-induced constipation (OIC).

  2. X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists.

    PubMed

    Xu, Wei; Huang, Jun-Jun; Shao, Bin-Hao; Xu, Xing-Jie; Jiang, Ren-Wang; Yuan, Mu

    2015-10-30

    Indole-arylpiperazine derivatives have exhibited good selectivity for the α1A-adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H···π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α1A antagonists with high selectivity.

  3. Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols.

    PubMed

    Tewes, Bastian; Frehland, Bastian; Schepmann, Dirk; Schmidtke, Kai-Uwe; Winckler, Thomas; Wünsch, Bernhard

    2010-11-15

    NR2B selective NMDA receptor antagonists with tetrahydro-3-benzazepine-1,7-diol scaffold have been designed by formal cleavage and reconstitution of the piperidine ring of the lead compound ifenprodil (1). The secondary amine 10 represents the central building block for the synthesis of more than 25 tetrahydro-3-benzazepin-1-ols. Generally 7-hydroxy derivatives display higher NR2B receptor affinities than the corresponding 7-benzyloxy compounds. A distance of four atoms (five bond lengths) between the basic amino group and the terminal aryl moiety led to highest NR2B affinity. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol (WMS-1410, 25) represents the most promising NR2B antagonist of this series showing a K(i)-value of 14nM. Compound 25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC(50)=18.4nM) and is metabolically more stable than ifenprodil. Up to a dose of 100mg/kg 25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay.

  4. Kisspeptin antagonists.

    PubMed

    Roseweir, Antonia Kathryn; Millar, Robert P

    2013-01-01

    Kisspeptin is now known to be an important regulator of the hypothalamic--pituitary-gonadal axis and is the target of a range of regulators, such as steroid hormone feedback, nutritional and metabolic regulation. Kisspeptin binds to its cognate receptor, KISS1R (also called GPR54), on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion-thus gating down-stream events supporting reproduction. The development of peripherally active kisspeptin antagonists could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer. The following chapter discusses the advances made in the search for both peptide and small molecule kisspeptin antagonists and their use in delineating the role of kisspeptin within the reproductive system. To date, four peptide antagonists and one small molecule antagonist have been designed.

  5. Structure-Activity Relationship Studies of Gonadotropin Releasing Hormone Antagonists Containing S-aryl/alkyl Norcysteines and their Oxidized Derivatives

    PubMed Central

    Samant, Manoj P.; White, Richard; Hong, Doley J.; Croston, Glenn; Conn, P. Michael; Janovick, Jo Ann; Rivier, Jean

    2008-01-01

    A series of acyline analogues incorporating l- and d- isomers of S-arylated/alkylated norcysteines [Ncy(R), where R is 2-naphthyl, methyl and isopropyl] at positions 1, 4, 7 and 10 were synthesized. Some of these analogues were mono- and di-oxidized to sulfoxides and sulfones. All of the analogues of acyline were screened for the antagonism of GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. Nine of the analogues (9, 11, 15, 16, 17, 19, 20, 21, and 22) had an antagonist potency (IC50 < 2 nM) similar to that of acyline (IC50 = 0.52 nM) in this assay. Selected analogues (9, 11, 15, 16, 19 and 21) were tested in vitro for their antagonism at the rat GnRH-R in a reporter gene assay as well as in an in vivo intact male rat assay. Analogues 9 and 15 were most potent in suppressing testosterone levels. PMID:17402723

  6. New substituted 1-(2,3-dihydrobenzo[1, 4]dioxin-2-ylmethyl)piperidin-4-yl derivatives with alpha(2)-adrenoceptor antagonist activity.

    PubMed

    Mayer, P; Brunel, P; Chaplain, C; Piedecoq, C; Calmel, F; Schambel, P; Chopin, P; Wurch, T; Pauwels, P J; Marien, M; Vidaluc, J L; Imbert, T

    2000-10-05

    The emergence of a novel theory concerning the role of noradrenaline in the progression and the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases has provided a new impetus toward the discovery of novel compounds acting at alpha(2)-adrenoceptors. A series of substituted 1-(2, 3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives bearing an amide, urea, or imidazolidinone moiety was studied. Some members of this series of compounds proved to be potent alpha(2)-adrenoceptor antagonists with good selectivity versus alpha(1)-adrenergic and D(2)-dopamine receptors. Particular emphasis is given to compound 33g which displays potent alpha(2)-adrenoceptor binding affinity in vitro and central effects in vivo following oral administration.

  7. Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists.

    PubMed

    Moritomo, Ayako; Yamada, Hiroyoshi; Watanabe, Toshihiro; Itahana, Hirotsune; Akuzawa, Shinobu; Okada, Minoru; Ohta, Mitsuaki

    2013-12-15

    To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.

  8. QSAR models for predicting the activity of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists derived from erythromycin A using quantum chemical properties.

    PubMed

    Fernández, Michael; Caballero, Julio

    2007-04-01

    Multiple linear regression (MLR) combined with genetic algorithm (GA) and Bayesian-regularized Genetic Neural Networks (BRGNNs) were used to model the binding affinity (pK(I)) of 38 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A for the Human Luteinizing Hormone-Releasing Hormone (LHRH) receptor using quantum chemical descriptors. A multiparametric MLR equation with good statistical quality was obtained that describes the features relevant for antagonistic activity when the substituent at the position 3 of the erythronolide core was varied. In addition, four-descriptor linear and nonlinear models were established for the whole dataset. Such models showed high statistical quality. However, the BRGNN model was better than the linear model according to the external validation process. In general, our linear and nonlinear models reveal that the binding affinity of the compounds studied for the LHRH receptor is modulated by electron-related terms.

  9. Amide derivatives of ethacrynic acid: synthesis and evaluation as antagonists of Wnt/beta-catenin signaling and CLL cell survival.

    PubMed

    Jin, Guangyi; Lu, Desheng; Yao, Shiyin; Wu, Christina C N; Liu, Jerry X; Carson, Dennis A; Cottam, Howard B

    2009-02-01

    A series of amides of ethacrynic acid was prepared and evaluated for their ability to inhibit Wnt signaling and decrease the survival of CLL cells. Several of the most potent derivatives were active in the low micromolar range. Reduction of the alpha,beta-unsaturated carbon-carbon double bond of EA abrogated both the inhibition of Wnt signaling as well as the decrease in CLL survival. Preliminary mechanism of action studies suggest that these derivatives covalently modify sulfhydryl groups present on transcription factors important for Wnt/beta-catenin signaling.

  10. Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays

    PubMed Central

    Kiris, Erkan; Nuss, Jonathan E.; Stanford, Stephanie M.; Wanner, Laura M.; Cazares, Lisa; Maestre, Michael F.; Du, Hao T.; Gomba, Glenn Y.; Burnett, James C.; Gussio, Rick; Bottini, Nunzio; Panchal, Rekha G.; Kane, Christopher D.; Tessarollo, Lino; Bavari, Sina

    2015-01-01

    There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists. PMID:26061731

  11. 1,4-Dihydropyridine derivatives without Ca2+-antagonist activity up-regulate Psma6 mRNA expression in kidneys of intact and diabetic rats.

    PubMed

    Ošiņa, Kristīne; Rostoka, Evita; Sokolovska, Jelizaveta; Paramonova, Natalia; Bisenieks, Egils; Duburs, Gunars; Sjakste, Nikolajs; Sjakste, Tatjana

    2016-01-01

    Impaired degradation of proteins by the ubiquitin-proteasome system (UPS) is observed in numerous pathologies including diabetes mellitus (DM) and its complications. Dysregulation of proteasomal degradation might be because of altered expression of genes and proteins involved in the UPS. The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A novel group of 1,4-dihydropyridine (1,4-DHP) derivatives lacking Ca2+-antagonists activities, but capable to produce antidiabetic, antioxidant and DNA repair enhancing effects, were tested for ability to modify Psma6 mRNA expression levels in rat kidneys and blood in healthy animals and in rats with streptozotocin (STZ) induced DM. Psma6 gene was chosen for the study, as polymorphisms of its human analogue are associated with DM and cardiovascular diseases. 1,4-DHP derivatives (metcarbatone, etcarbatone, glutapyrone, J-9-125 and AV-153-Na) were administered per os for three days (0.05 mg/kg and/or 0.5 mg/kg). Psma6 gene expression levels were evaluated by quantitative PCR. Psma6 expression was higher in kidneys compared to blood. Induction of diabetes caused increase of Psma6 expression in kidneys, although it was not changed in blood. Several 1,4-DHP derivatives increased expression of the gene both in kidneys and blood of control and model animals, but greater impact was observed in kidneys. The observed effect might reflect coupling of antioxidant and proteolysis-promoting activities of the compounds.

  12. Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism

    NASA Technical Reports Server (NTRS)

    Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

    2003-01-01

    Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.

  13. Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte-Derived Dendritic Cells to RNA Virus Infection

    PubMed Central

    Yen, Benjamin C.

    2016-01-01

    ABSTRACT Dendritic cells (DCs) are major targets of filovirus infection in vivo. Previous studies have shown that the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) suppress DC maturation in vitro. Both viruses also encode innate immune evasion functions. The EBOV VP35 (eVP35) and the MARV VP35 (mVP35) proteins each can block RIG-I-like receptor signaling and alpha/beta interferon (IFN-α/β) production. The EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins each inhibit the production of IFN-stimulated genes (ISGs) by blocking Jak-STAT signaling; however, this occurs by different mechanisms, with eVP24 blocking nuclear import of tyrosine-phosphorylated STAT1 and mVP40 blocking Jak1 function. MARV VP24 (mVP24) has been demonstrated to modulate host cell antioxidant responses. Previous studies demonstrated that eVP35 is sufficient to strongly impair primary human monocyte-derived DC (MDDC) responses upon stimulation induced through the RIG-I-like receptor pathways. We demonstrate that mVP35, like eVP35, suppresses not only IFN-α/β production but also proinflammatory responses after stimulation of MDDCs with RIG-I activators. In contrast, eVP24 and mVP40, despite suppressing ISG production upon RIG-I activation, failed to block upregulation of maturation markers or T cell activation. mVP24, although able to stimulate expression of antioxidant response genes, had no measurable impact of DC function. These data are consistent with a model where filoviral VP35 proteins are the major suppressors of DC maturation during filovirus infection, whereas the filoviral VP24 proteins and mVP40 are insufficient to prevent DC maturation. IMPORTANCE The ability to suppress the function of dendritic cells (DCs) likely contributes to the pathogenesis of disease caused by the filoviruses Ebola virus and Marburg virus. To clarify the basis for this DC suppression, we assessed the effect of filovirus proteins known to antagonize innate immune signaling pathways, including Ebola

  14. Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice.

    PubMed

    Kim, Sun-Don; Kim, Ha-Neui; Lee, Jong-Ho; Jin, Won Jong; Hwang, Soon Jung; Kim, Hong-Hee; Ha, Hyunil; Lee, Zang Hee

    2013-09-15

    Trapidil, a platelet-derived growth factor antagonist, was originally developed as a vasodilator and anti-platelet agent and has been used to treat patients with ischemic coronary heart, liver, and kidney disease. In this study, we investigated the effects of trapidil on osteoclastogenesis and elucidated the possible mechanism of action of trapidil. Trapidil strongly inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblasts without affecting receptor activator of NF-κB ligand (RANKL) or osteoprotegerin expression in osteoblasts. In addition, trapidil suppressed RANKL-induced osteoclast formation from osteoclast precursors. Trapidil reduced RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis, without affecting the expression of c-Fos that functions as a key upstream activator of NFATc1 during osteoclastogenesis. Ectopic expression of a constitutively active form of NFATc1 reversed the anti-osteoclastogenic effect of trapidil, indicating that NFATc1 is a critical target of the anti-osteoclastogenic action of trapidil. RANKL-induced calcium oscillation and Pim-1 expression, which are required for NFATc1 induction and osteoclastogenesis, were abrogated by trapidil. Consistent with the in vitro results, trapidil had a potent inhibitory effect on osteoclast formation and bone resorption induced by interleukin-1 in an animal model. Taken together, our data demonstrate that trapidil abrogates RANKL-induced calcium oscillation and Pim-1 expression required for NFATc1 induction, thereby inhibiting osteoclastogenesis.

  15. A Structure-Activity Relationship Study of Imidazole-5-Carboxylic Acid Derivatives as Angiotensin II Receptor Antagonists Combining 2D and 3D QSAR Methods.

    PubMed

    Sharma, Mukesh C

    2016-03-01

    Two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies were performed for correlating the chemical composition of imidazole-5-carboxylic acid analogs and their angiotensin II [Formula: see text] receptor antagonist activity using partial least squares and k-nearest neighbor, respectively. For comparing the three different feature selection methods of 2D-QSAR, k-nearest neighbor models were used in conjunction with simulated annealing (SA), genetic algorithm and stepwise coupled with partial least square (PLS) showed variation in biological activity. The statistically significant best 2D-QSAR model having good predictive ability with statistical values of [Formula: see text] and [Formula: see text] was developed by SA-partial least square with the descriptors like [Formula: see text]count, 5Chain count, SdsCHE-index, and H-acceptor count, showing that increase in the values of these descriptors is beneficial to the activity. The 3D-QSAR studies were performed using the SA-PLS. A leave-one-out cross-validated correlation coefficient [Formula: see text] and predicate activity [Formula: see text] = 0.7226 were obtained. The information rendered by QSAR models may lead to a better understanding of structural requirements of substituted imidazole-5-carboxylic acid derivatives and also aid in designing novel potent antihypertensive molecules.

  16. Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition.

    PubMed

    Sato, Ippei; Morihira, Koichiro; Inami, Hiroshi; Kubota, Hirokazu; Morokata, Tatsuaki; Suzuki, Keiko; Iura, Yosuke; Nitta, Aiko; Imaoka, Takayuki; Takahashi, Toshiya; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-Ichi

    2008-09-15

    In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.

  17. Three-dimensional quantitative structure-activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists.

    PubMed

    Morales-Bayuelo, Alejandro; Ayazo, Hernan; Vivas-Reyes, Ricardo

    2010-10-01

    Comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were performed on a series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists (MCHR1 antagonists). Molecular superimposition of antagonists on the template structure was performed by database alignment method. The statistically significant model was established on sixty five molecules, which were validated by a test set of ten molecules. The CoMSIA model yielded the best predictive model with a q(2) = 0.639, non cross-validated R(2) of 0.953, F value of 92.802, bootstrapped R(2) of 0.971, standard error of prediction = 0.402, and standard error of estimate = 0.146 while the CoMFA model yielded a q(2) = 0.680, non cross-validated R(2) of 0.922, F value of 114.351, bootstrapped R(2) of 0.925, standard error of prediction = 0.364, and standard error of estimate = 0.180. CoMFA analysis maps were employed for generating a pseudo cavity for LeapFrog calculation. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. The results show the variability of steric and electrostatic contributions that determine the activity of the MCHR1 antagonist, with these results we proposed new antagonists that may be more potent than previously reported, these novel antagonists were designed from the addition of highly electronegative groups in the substituent di(i-C(3)H(7))N- of the bicycle [4.1.0] heptanes, using the model CoMFA which also was used for the molecular design using the technique LeapFrog. The data generated from the present study will further help to design novel, potent, and selective MCHR1 antagonists.

  18. Inhibition of mediator release in RBL-2H3 cells by some H1-antagonist derived anti-allergic drugs: relation to lipophilicity and membrane effects.

    PubMed

    Fischer, M J; Paulussen, J J; Horbach, D A; Roelofsen, E P; van Miltenburg, J C; de Mol, N J; Janssen, L H

    1995-02-01

    In a model for mucosal mast cells (RBL-2H3 cells) a set H1-antagonist derived anti-allergic drugs containing a diphenylmethyl piperazinyl moiety was examined for their ability to inhibit release of the mediator beta-hexosaminidase. Cells were activated with antigen or the calcium ionophore A23187, whether or not in combination with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Oxatomide, hydroxyzine and cetirizine inhibit the antigen induced beta-hexosaminidase release. The release triggered by A23187, whether or not in combination with TPA is hardly influenced by the compounds. A biphasic dependence of the inhibition of exocytosis in RBL cells on lipophilicity is observed with the optimum at log P is 5-6. The extremely lipophilic compounds meclozine and buclizine are not active in this model. pH dependence of the effect of the drugs shows that especially the uncharged species are active in inhibiting exocytosis. The investigated compounds show an effect on phase transitions in L-alpha-phosphatidylcholine dipalmitoyl liposomes as assayed with differential scanning calorimetry (DSC). For the less extremely lipophilic compounds the induced changes in the phospholipid membranes increased with lipophilicity. The relation between structural features of the drug and the interaction with phospholipids is discussed in view of the DSC results. We conclude that location of the active drugs at the membrane or the membrane/protein interface is important for the inhibiting activity on exocytosis. This could affect several membrane related processes, which are abundant in the early phases of the IgE-mediated signal transduction process.

  19. Synthesis and structure-activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists.

    PubMed

    Sato, Ippei; Morihira, Koichiro; Inami, Hiroshi; Kubota, Hirokazu; Morokata, Tatsuaki; Suzuki, Keiko; Hamada, Noritaka; Iura, Yosuke; Nitta, Aiko; Imaoka, Takayuki; Takahashi, Toshiya; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-ichi

    2008-01-01

    A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.

  20. ACTH Antagonists

    PubMed Central

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  1. Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration.

    PubMed

    Minghetti, Luisa; Greco, Anita; Potenza, Rosa Luisa; Pezzola, Antonella; Blum, David; Bantubungi, Kadiombo; Popoli, Patrizia

    2007-05-01

    Inhibition of adenosine A2A receptors (A2ARs) is neuroprotective in several experimental models of striatal diseases. However, the mechanisms elicited by A2AR blockade are only partially known, and critical aspects about the potential beneficial effects of A2AR antagonism in models of neurodegeneration still await elucidation. In the present study, we analyzed the influence of the selective A2AR antagonist SCH 58261 in a rat model of striatal excitotoxicity obtained by unilateral intrastriatal injection of quinolinic acid (QA). We found that SCH 58261 differently affected the expression of cyclooxygenase-2 (COX-2) induced by QA in cortex and striatum. The antagonist enhanced COX-2 expression in cortical neurons and prevented it in striatal microglia-like cells. Similarly, SCH 58261 differently regulated astrogliosis and microglial activation in the 2 brain regions. In addition, the A2AR antagonist prevented the QA-induced increase in striatal brain-derived neurotrophic factor levels. Because COX-2 activity has been linked to excitotoxic processes and because brain-derived neurotrophic factor depletion has been observed in mouse models as well as in patients with Huntington disease, we suggest that the final outcome of A2AR blockade (namely neuroprotection vs neurodegeneration) is likely to depend on the balance among its various and region-specific effects.

  2. Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists.

    PubMed

    Yuan, Yunyun; Elbegdorj, Orgil; Chen, Jianyang; Akubathini, Shashidhar K; Beletskaya, Irina O; Selley, Dana E; Zhang, Yan

    2011-09-15

    Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate 'address' domain may exist in the mu opioid receptor, which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor.

  3. Structure Selectivity Relationship Studies of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan Derivatives Toward the Development of the Mu Opioid Receptor Antagonists

    PubMed Central

    Yuan, Yunyun; Elbegdorj, Orgil; Chen, Jianyang; Akubathini, Shashidhar K.; Beletskaya, Irina O.; Selley, Dana E.; Zhang, Yan

    2011-01-01

    Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate “address” domain may exist in the mu opioid receptor, which favours the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor. PMID:21788135

  4. Novel opioid peptide derived antagonists containing (2S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2S)-Mdcp].

    PubMed

    Ghosh, Animesh; Luo, Jie; Liu, Chen; Weltrowska, Grazyna; Lemieux, Carole; Chung, Nga N; Lu, Yixin; Schiller, Peter W

    2008-09-25

    A synthesis of the novel tyrosine analogue (2 S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2 S)-Mdcp] (15) was developed. In (2 S)-Mdcp, the amino and hydroxyl groups of 2',6'-dimethyltyrosine are replaced by a methyl and a carbamoyl group, respectively, and its substitution for Tyr (1) in opioid agonist peptides resulted in compounds showing antagonism at all three opioid receptors. The cyclic peptide (2 S)-Mdcp-c[D-Cys-Gly-Phe(pNO 2)-D-Cys]NH 2 (1) was a potent and selective mu antagonist, whereas (2 S)-Mdcp-c[D-Pen-Gly-Phe(pF)-Pen]-Phe-OH (3) showed subnanomolar delta antagonist activity and extraordinary delta selectivity.

  5. Γ-aminobutyric acid(C) (GABAC) selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: amides and hydroxamates.

    PubMed

    Locock, Katherine E S; Yamamoto, Izumi; Tran, Priscilla; Hanrahan, Jane R; Chebib, Mary; Johnston, Graham A R; Allan, Robin D

    2013-07-11

    Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4-ACPHA (10a, IC50 = 13 μM) and 4-ACPAM (11a, IC50 = 10 μM). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.

  6. Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: exploration and optimization of alternative pyrazole structure.

    PubMed

    Sugimoto, Yuichi; Kobayashi, Kensuke; Asai, Masanori; Ohno, Akio; Yamada, Koji; Ozaki, Satoshi; Ohta, Hisashi; Okamoto, Osamu

    2009-08-15

    Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure-activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.

  7. The computational design of test compounds with potentially specific biological activity: Histamine-H2 agonists derived from 5-HT/H2 antagonists

    NASA Astrophysics Data System (ADS)

    Topiol, Sid; Sabio, Michael

    1991-06-01

    The previously proposed models for the recognition and activation of 5-HT and histamine-H2 receptors, which were employed to explain the antagonist activity of LSD at both of these receptors, as well as the selective antagonism for H2 receptors by SKF-10856 and 9,10-dihydro-LSD, are used herein to design a compound to test the H2-receptor model. The design strategy attempts to construct a compound with potentially selective H2 agonism. The design scheme maintains features which were previously used to explain selective recognition of SKF-10856 and 9,10-dihydro-LSD as well as reintroduces the chemical features proposed to be responsible for H2 activation. The existence of the H2 recognition and activation features in the proposed compound is verified, in a previously proposed model, by computational studies of the molecular electrostatic potentials and shifts in the tautomeric preference.

  8. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.

    PubMed

    Neumeyer, J L; Bidlack, J M; Zong, R; Bakthavachalam, V; Gao, P; Cohen, D J; Negus, S S; Mello, N K

    2000-01-13

    This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

  9. Assessment in pig coronary artery of long-lasting and potent calcium antagonistic actions of the novel dihydropyridine derivative mepirodipine hydrochloride.

    PubMed

    Nakayama, K; Kashiwabara, T; Yamada, S; Tanaka, Y

    1989-01-01

    Ca antagonistic properties of mepirodipine hydrochloride [+)-(3'S,4S)-3-(1'-benzyl-3'-pyrrolidinyl methyl 2,6-dimethyl-4- (m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, YM-09730-5) were assessed by studying the pharmacological actions and binding characteristics of the drug in the stem coronary artery. IC50 values of YM-09730-5 (3.5 x 10(-10) mol/l) and nifedipine (6.6 x 10(-9) mol/l) for 40 mmol/l K-induced tonic contraction of pig coronary artery indicated that YM-09730-5 was about 20 times more potent than nifedipine in Ca antagonistic action. However, YM-09730-5 showed an onset of inhibitory action 3 to 5 times slower than nifedipine. A 40-min preincubation of the target tissue with YM-09730-5 also inhibited the contractions produced by acetylcholine, histamine, 5-hydroxytryptamine, and high Ca, and pD2' values were between 8.0 and 7.0; while nifedipine was less potent. The specific binding of [3H]nitrendipine to the membrane of pig coronary artery was inhibited by YM-09730-5, thereby indicating that [3H]nitrendipine and YM-09730-5 compete for the similar receptor sites of dihydropyridine-sensitive Ca channels. Suppression of high K-, Ca- and agonist-induced contractions by YM-09730-5 (3 x 10(-9) mol/l-10(-7) mol/l) remained even after washings at 20-min intervals for more than 3 h; and, in particular at a high concentration of YM-09730-5, the suppression was slightly antagonized by excess Ca or a Ca-agonist. The contraction inhibited by nifedipine, on the other hand, was readily restored by several washings.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. 7-Substituted-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as antagonists of the transient receptor potential ankyrin 1 (TRPA1) channel: a promising approach for treating pain and inflammation.

    PubMed

    Baraldi, Pier Giovanni; Romagnoli, Romeo; Saponaro, Giulia; Aghazadeh Tabrizi, Mojgan; Baraldi, Stefania; Pedretti, Pamela; Fusi, Camilla; Nassini, Romina; Materazzi, Serena; Geppetti, Pierangelo; Preti, Delia

    2012-03-01

    The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N(7)-phenylacetamide or N(7)-[4-(substituted-phenyl)-thiazol-2-yl]-acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC(50)=400nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain.

  11. Synthesis and biological evaluation of novel 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as sigma-1 (σ1) receptor antagonists for the treatment of pain.

    PubMed

    Lan, Yu; Songyang, Yiyan; Zhang, Lingli; Peng, Yan; Song, Jinchun

    2016-04-15

    The synthesis and biological evaluation of new series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as selective sigma-1 receptor (σ1R) antagonists are reported. The receptor affinities of new compounds were evaluated in vitro in σ1 and σ2 receptor binding assays. The structure-active relationship study leads us to the most promising compound: 2-(4-chlorophenyl)-4-(3-(4-methylpiperidin-1-yl)propoxy)-5,6,7,8-tetra-hydroquinazoline (33). Compound 33 has exerted nanomolar affinity for σ1R (Kiσ1=15.6 nM) and high σ1/σ2 selectivity (Kiσ2 >2000 nM), and identified to be a σ1R antagonist. In animal model, compound 33 exhibited dose dependent anti-nociceptive effects in the formalin test. These results suggest that compound 33 could be a potent analgesic for pain treatment.

  12. Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan.

    PubMed

    Neumeyer, J L; Gu, X H; van Vliet, L A; DeNunzio, N J; Rusovici, D E; Cohen, D J; Negus, S S; Mello, N K; Bidlack, J M

    2001-10-22

    A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (mu, delta, and kappa) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the mu and kappa opioid receptors was observed. All of these novel derivatives showed a preference for the mu and kappa versus delta binding.

  13. Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

    PubMed Central

    Zhang, Qi; Guo, Fei; Fu, Zhi-wen; Zhang, Bing; Huang, Cheng-gang; Li, Yang

    2016-01-01

    Aim: N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. Methods: NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg−1·d−1) or a positive-control drug, fluoxetine (10 mg·kg−1·d−1) for 3 weeks. Behavioral assessments were carried out every week. Results: In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. Conclusion: YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression. PMID:26687936

  14. Design, synthesis, and pharmacological evaluation of 5-oxo-1,2,4-oxadiazole derivatives as AT1 antagonists with antihypertension activities.

    PubMed

    Zhu, Weibo; Bao, Xiaolu; Ren, He; Liao, Pingyong; Zhu, Wei; Yan, Yijia; Wang, Li; Chen, Zhilong

    A series of new 5-oxo-1,2,4-oxadiazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole group was designed, synthesized, and pharmacologically evaluated. These derivatives displayed high affinities to the AT1 receptor at the same order of magnitude to losartan. The methyl ester with 1, 4-disubsituted indole group, 1 (5.01 ± 1.67 nM) showed high antihypertension activity on spontaneously hypertensive rats (SHRs). Its maximal response lowered 30 mmHg of mean blood pressure (MBP) at 10 mg/kg after oral administration, which was better than irbesartan, and the antihypertensive effect lasted beyond 24 h. These results made 1 deserve further investigation.

  15. Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist.

    PubMed

    Shirayama, Yukihiko; Yang, Chun; Zhang, Ji-chun; Ren, Qian; Yao, Wei; Hashimoto, Kenji

    2015-12-01

    Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.

  16. Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists.

    PubMed

    Lingam, V S Prasadarao; Dahale, Dnyaneshwar H; Rathi, Vijay E; Shingote, Yogesh B; Thakur, Rajni R; Mindhe, Ajit S; Kummari, Srinivas; Khairatkar-Joshi, Neelima; Bajpai, Malini; Shah, Daisy M; Sapalya, Ratika S; Gullapalli, Srinivas; Gupta, Praveen K; Gudi, Girish S; Jadhav, Satyawan B; Pattem, Rambabu; Thomas, Abraham

    2015-10-22

    We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng · h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.

  17. Muscarinic Receptor Antagonists.

    PubMed

    Matera, Maria Gabriella; Cazzola, Mario

    2017-01-01

    Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD) and asthma and appears to be the major reversible component of airway obstruction. Therefore, treatment with muscarinic receptor antagonists is an effective bronchodilator therapy in COPD and also in asthmatic patients. In recent years, the accumulating evidence that the cholinergic system controls not only contraction by airway smooth muscle but also the functions of inflammatory cells and airway epithelial cells has suggested that muscarinic receptor antagonists could exert other effects that may be of clinical relevance when we must treat a patient suffering from COPD or asthma. There are currently six muscarinic receptor antagonists licenced for use in the treatment of COPD, the short-acting muscarinic receptor antagonists (SAMAs) ipratropium bromide and oxitropium bromide and the long-acting muscarinic receptor antagonists (LAMAs) aclidinium bromide, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide. Concerns have been raised about possible associations of muscarinic receptor antagonists with cardiovascular safety, but the most advanced compounds seem to have an improved safety profile. Further beneficial effects of SAMAs and LAMAs are seen when added to existing treatments, including LABAs, inhaled corticosteroids and phosphodiesterase 4 inhibitors. The importance of tiotropium bromide in the maintenance treatment of COPD, and likely in asthma, has spurred further research to identify new LAMAs. There are a number of molecules that are being identified, but only few have reached the clinical development.

  18. Structural, conformational, biochemical, and pharmacological study of some amides derived from 3,7-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-amine as potential 5-HT 3 receptor antagonists

    NASA Astrophysics Data System (ADS)

    Fernández, M. J.; Huertas, R. M.; Gálvez, E.; Orjales, A.; Berisa, A.; Labeaga, L.; Garcia, A. G.; Uceda, G.; Server-Carrió, J.; Martinez-Ripoll, M.

    1995-12-01

    A series of amides derived from 3,7-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-amine have been synthesized and examined by 1H and 13C NMR spectroscopy and the crystal structure of 9-(2,4,6-trichlorobenzamido)-3,7-dimethyl-3,7-diazabicyclo[3.3.1] nonane hydrochloride ( 4a·HCl) has been determined by X-ray diffraction. These compounds adopt an almost perfect chair-chair conformation with the NCH 3 groups in equatorial position. This conformation is nearly the same as that observed for compound 4a in the solid state. From binding studies of compounds 4a-c, compound 4b demonstrated the ability to efficiently displace [ 3H]GR65630 bound to bovine brain area postrema membranes to an extent comparable to MDL 72222. In the von Bezold-Jarish reflex, compound 4b showed significant results at a dose of 25 mg Kg -1. It is shown for the first time that a series of compounds with a bispidine skeleton linked through an amide moiety to several aromatic rings, shows 5-HT 3 antagonistic profiles.

  19. Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists with longer durations of action.

    PubMed

    Jimonet, P; Bohme, G A; Bouquerel, J; Boireau, A; Damour, D; Debono, M W; Genevois-Borella, A; Hardy, J C; Hubert, P; Manfré, F; Nemecek, P; Pratt, J; Randle, J C; Ribeill, Y; Stutzmann, J M; Vuilhorgne, M; Mignani, S

    2001-01-22

    A novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosphonic acid 4i exhibited a strong and a selective binding affinity for the AMPA receptor (IC50 = 13 nM) and demonstrated potent antagonist activity (IC50 = 6nM) at the ionotropic AMPA receptor. This compound also displayed good anticonvulsant properties against electrically-induced convulsions after ip and iv administration with ED50 values between 0.8 and 1 mg/kg. Furthermore, a strong increase in potency was observed when given iv 3 h before test (ED50 = 3.5 instead of 25.6 mg/kg for the corresponding 9-carboxymethyl-2-carboxylic acid analogue). These data confirmed that there is an advantage in replacing the classical carboxy substituents by their bioisosteres such as tetrazole or phosphonic acid groups.

  20. MOLECULAR PROBES FOR EXTRACELLULAR ADENOSINE RECEPTORS

    PubMed Central

    Jacobson, Kenneth A.; Ukena, Dieter; Padgett, William; Kirk, Kenneth L.; Daly, John W.

    2012-01-01

    Derivatives of adenosine receptor agonists (N6-phenyladenosines) and antagonists (1,3-dialkyl-8-phenylxanthines) bearing functionalized chains suitable for attachment to other molecules have been reported [Jacobson et al., J. med. Chem. 28, 1334 and 1341 (1985)]. The “functionalized congener” approach has been extended to the synthesis of spectroscopic and other probes for adenosine receptors that retain high affinity (Ki ~ 10−9 −10−8 M) in A1-receptor binding. The probes have been synthesized from an antagonist xanthine amine congener (XAC) and an adenosine amine congener (ADAC). [3H]ADAC has been synthesized and found to bind highly specifically to A1-adenosine receptors of rat and calf cerebral cortical membranes with KD values of 1.4 and 0.34 nM respectively. The higher affinity in the bovine brain, seen also with many of the probes derived from ADAC and XAC, is associated with phenyl substituents. The spectroscopic probes contain a reporter group attached at a distal site of the functionalized chain. These bifunctional ligands may contain a spin label (e.g. the nitroxyl radical TEMPO) for electron spin resonance spectroscopy, or a fluorescent dye, including fluorescein and 4-nitrobenz-2-oxa-1,3-diazole (NBD), or labels for 19F nuclear magnetic resonance spectroscopy. Potential applications of the spectroscopic probes in characterization of adenosine receptors are discussed. PMID:3036153

  1. Rational discovery of novel nuclear hormone receptor antagonists

    NASA Astrophysics Data System (ADS)

    Schapira, Matthieu; Raaka, Bruce M.; Samuels, Herbert H.; Abagyan, Ruben

    2000-02-01

    Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor- by using information derived from antagonist-bound estrogen receptor-α and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

  2. Studies on quinazolines. 5. 2,3-dihydroimidazo[1,2-c]quinazoline derivatives: a novel class of potent and selective alpha 1-adrenoceptor antagonists and antihypertensive agents.

    PubMed

    Chern, J W; Tao, P L; Yen, M H; Lu, G Y; Shiau, C Y; Lai, Y J; Chien, S L; Chan, C H

    1993-07-23

    A series of 2-[(substituted phenylpiperazin-1-yl)methyl]- and 2-[(substituted phenylpiperidin-1-yl)methyl]-2,3-dihydroimidazo[1,2- c]quinazolin-5(6H)-ones or -5(6H)-thiones, and 3-[(substituted phenylpiperazin-1-yl)methyl]-2,3-dihydroimidazo[1,2-c]quinaz oline derivatives were synthesized, as conformationally restricted analogues of SGB-1534 and ketanserin, for evaluation as alpha-antagonists and antihypertensive agents. Most compounds containing a (substituted phenylipiperazinyl)methyl side chain displayed high binding affinity for alpha 1-adrenoceptor with no significant activity at alpha 2-sites. Compounds having a (substituted phenylpiperazinyl)methyl at the 3-position of 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ring system had a better activity than those with the same substituent at the 2-position. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented and indicate that compounds with substitution at the ortho position on the benzene ring of the phenylpiperazine side chain moiety are more potent than those without substitution and/or substitutions at the 3- and 4-positions. Computer-assisted superimposition of SGB-1534 and 20b showed little structural correspondence between the quinazolinone and 2,3-dihydroimidazo[1,2-c]quinazoline nucleus, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Antihypertensive activity was evaluated via intravenous administration of each compound to spontaneously hypertensive rats, and compounds (16a, 16b, 20b, and 28b) illustrated similar efficacy to SGB-1534 when assessed after 6 h. The pA2 value for 16a against phenylephedrine in rat aorta was much higher than that of prazosin. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compounds 20b and 28b warrant further evaluation.

  3. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  4. Advantages of an antagonist: bicuculline and other GABA antagonists

    PubMed Central

    Johnston, Graham AR

    2013-01-01

    The convulsant alkaloid bicuculline continues to be investigated more than 40 years after the first publication of its action as an antagonist of receptors for the inhibitory neurotransmitter GABA. This historical perspective highlights key aspects of the discovery of bicuculline as a GABA antagonist and the sustained interest in this and other GABA antagonists. The exciting advances in the molecular biology, pharmacology and physiology of GABA receptors provide a continuing stimulus for the discovery of new antagonists with increasing selectivity for the myriad of GABA receptor subclasses. Interesting GABA antagonists not structurally related to bicuculline include gabazine, salicylidene salicylhydrazide, RU5135 and 4-(3-biphenyl-5-(4-piperidyl)-3-isoxazole. Bicuculline became the benchmark antagonist for what became known as GABAA receptors, but not all ionotropic GABA receptors are susceptible to bicuculline. In addition, not all GABAA receptor antagonists are convulsants. Thus there are still surprises in store as the study of GABA receptors evolves. PMID:23425285

  5. alpha2-Adrenoreceptor antagonists.

    PubMed

    Mayer, P; Imbert, T

    2001-06-01

    A review of the literature relating to the therapeutic potential of alpha2-adrenoceptor antagonists published between 1990 and 2000 is presented. Although extensively studied since the early 1970s in a wide spectrum of therapeutic applications, the distinction of alpha2-adrenoceptor subtypes and some emerging evidence concerning new applications in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, obesity and schizophrenia, have refreshed an interest in this class of agents.

  6. Synthesis and structure-activity relationships of a new model of arylpiperazines. 5. Study of the physicochemical influence of the pharmacophore on 5-HT(1a)/alpha(1)-adrenergic receptor affinity: synthesis of a new derivative with mixed 5-HT(1a)/d(2) antagonist properties.

    PubMed

    López-Rodríguez, M L; Morcillo, M J; Fernández, E; Porras, E; Orensanz, L; Beneytez, M E; Manzanares, J; Fuentes, J A

    2001-01-18

    In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT(1A) and alpha(1)-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin or a diketopiperazine (X = -(CH(2))(3)-, -(CH(2))(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT(1A) and alpha(1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationships (QSAR) and neural networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT(1A): K(i) = 27 nM; alpha(1): K(i) > 1000 nM). This derivative displays affinity for the dopamine D(2) receptor (K(i) = 22 nM) and is selective versus all other receptors examined (5-HT(2A), 5-HT(3), 5-HT(4) and Bz; K(i) > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT(1A) receptor sites and as an antagonist in the dopamine D(2) receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT(1A)/D(2) antagonist properties and this derivative could be useful as a pharmacological tool.

  7. New potential uroselective NO-donor alpha1-antagonists.

    PubMed

    Boschi, Donatella; Tron, Gian Cesare; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto; Poggesi, Elena; Motta, Gianni; Leonardi, Amedeo

    2003-08-14

    A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.

  8. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  9. Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists.

    PubMed

    Didiuk, Mary T; Griffith, David A; Benbow, John W; Liu, Kevin K C; Walker, Daniel P; Bi, F Christopher; Morris, Joel; Guzman-Perez, Angel; Gao, Hua; Bechle, Bruce M; Kelley, Ryan M; Yang, Xiaojing; Dirico, Kenneth; Ahmed, Syed; Hungerford, William; DiBrinno, Joseph; Zawistoski, Michael P; Bagley, Scott W; Li, Jianke; Zeng, Yuan; Santucci, Stephanie; Oliver, Robert; Corbett, Matthew; Olson, Thanh; Chen, Chiliu; Li, Mei; Paralkar, Vishwas M; Riccardi, Keith A; Healy, David R; Kalgutkar, Amit S; Maurer, Tristan S; Nguyen, Hang T; Frederick, Kosea S

    2009-08-15

    Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.

  10. Small molecule antagonists for chemokine CCR3 receptors.

    PubMed

    Willems, Lianne I; Ijzerman, Ad P

    2010-09-01

    The chemokine receptor CCR3 is believed to play a role in the development of allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis. Despite the conflicting results that have been reported regarding the importance of eosinophils and CCR3 in allergic inflammation, inhibition of this receptor with small molecule antagonists is thought to provide a valuable approach for the treatment of these diseases. This review describes the structure-activity relationships (SAR) of small molecule CCR3 antagonists as reported in the scientific and patent literature. Various chemical classes of small molecule CCR3 antagonists have been described so far, including (bi)piperidine and piperazine derivatives, N-arylalkylpiperidine urea derivatives and (N-ureidoalkyl)benzylpiperidines, phenylalanine derivatives, morpholinyl derivatives, pyrrolidinohydroquinazolines, arylsulfonamides, amino-alkyl amides, imidazole- and pyrimidine-based antagonists, and bicyclic diamines. The (N-ureidoalkyl)benzylpiperidines are the best studied class in view of their generally high affinity and antagonizing potential. For many of these antagonists subnanomolar IC(50) values were reported for binding to CCR3 along with the ability to effectively inhibit intracellular calcium mobilization and eosinophil chemotaxis induced by CCR3 agonist ligands in vitro.

  11. Small Molecule CXCR3 Antagonists.

    PubMed

    Andrews, Stephen P; Cox, Rhona J

    2016-04-14

    Chemokines and their receptors are known to play important roles in disease. More than 40 chemokine ligands and 20 chemokine receptors have been identified, but, to date, only two small molecule chemokine receptor antagonists have been approved by the FDA. The chemokine receptor CXCR3 was identified in 1996, and nearly 20 years later, new areas of CXCR3 disease biology continue to emerge. Several classes of small molecule CXCR3 antagonists have been developed, and two have shown efficacy in preclinical models of inflammatory disease. However, only one CXCR3 antagonist has been evaluated in clinical trials, and there remain many opportunities to further investigate known classes of CXCR3 antagonists and to identify new chemotypes. This Perspective reviews the known CXCR3 antagonists and considers future opportunities for the development of small molecules for clinical evaluation.

  12. Tumor vasculature is regulated by FGF/FGFR signaling-mediated angiogenesis and bone marrow-derived cell recruitment: this mechanism is inhibited by SSR128129E, the first allosteric antagonist of FGFRs.

    PubMed

    Fons, Pierre; Gueguen-Dorbes, Geneviève; Herault, Jean-Pascal; Geronimi, Fabien; Tuyaret, Joël; Frédérique, Dol; Schaeffer, Paul; Volle-Challier, Cécile; Herbert, Jean-Marc; Bono, Françoise

    2015-01-01

    Tumor angiogenesis is accompanied by vasculogenesis, which is involved in the differentiation and mobilization of human bone marrow cells. In order to further characterize the role of vasculogenesis in the tumor growth process, the effects of FGF2 on the differentiation of human bone marrow AC133(+) cells (BM-AC133(+)) into vascular precursors were studied in vitro. FGF2, like VEGFA, induced progenitor cell differentiation into cell types with endothelial cell characteristics. SSR128129E, a newly discovered specific FGFR antagonist acting by allosteric interaction with FGFR, abrogated FGF2-induced endothelial cell differentiation, showing that FGFR signaling is essential during this process. To assess the involvement of the FGF/FRGR signaling in vivo, the pre-clinical model of Lewis lung carcinoma (LL2) in mice was used. Subcutaneous injection of LL2 cells into mice induced an increase of circulating EPCs from peripheral blood associated with tumor growth and an increase of intra-tumoral vascular index. Treatment with the FGFR antagonist SSR128129E strongly decreased LL2 tumor growth as well as the intra-tumoral vascular index (41% and 50% decrease vs. vehicle-treated mice respectively, P < 0.01). Interestingly, SSR128129E treatment significantly decreased the number of circulating EPCs from the peripheral blood (53% inhibition vs. vehicle-treated mice, P < 0.01). These results demonstrate for the first time that the blockade of the FGF/FGFR pathway by SSR128129E reduces EPC recruitment during angiogenesis-dependent tumor growth. In this context, circulating EPCs could be a reliable surrogate marker for tumor growth and angiogenic activity.

  13. Oxygen glucose deprivation causes mitochondrial dysfunction in cultivated rat hippocampal slices: protective effects of CsA, its immunosuppressive congener [D-Ser](8)CsA, the novel non-immunosuppressive cyclosporin derivative Cs9, and the NMDA receptor antagonist MK 801.

    PubMed

    Trumbeckaite, Sonata; Gizatullina, Zemfira; Arandarcikaite, Odeta; Röhnert, Peter; Vielhaber, Stefan; Malesevic, Miroslav; Fischer, Gunter; Seppet, Enn; Striggow, Frank; Gellerich, Frank Norbert

    2013-09-01

    We have introduced a sensitive method for studying oxygen/glucose deprivation (OGD)-induced mitochondrial alterations in homogenates of organotypic hippocampal slice cultures (slices) by high-resolution respirometry. Using this approach, we tested the neuroprotective potential of the novel non-immunosuppressive cyclosporin (CsA) derivative Cs9 in comparison with CsA, the immunosuppressive CsA analog [D-Ser](8)CsA, and MK 801, a N-methyl-d-aspartate (NMDA) receptor antagonist. OGD/reperfusion reduced the glutamate/malate dependent (and protein-related) state 3 respiration to 30% of its value under control conditions. All of the above drugs reversed this effect, with an increase to >88% of the value for control slices not exposed to OGD. We conclude that Cs9, [D-Ser](8)CsA, and MK 801, despite their different modes of action, protect mitochondria from OGD-induced damage.

  14. Boosting Adaptive Immunity: A New Role for PAFR Antagonists

    PubMed Central

    Koga, Marianna M.; Bizzarro, Bruna; Sá-Nunes, Anderson; Rios, Francisco J.; Jancar, Sonia

    2016-01-01

    We have previously shown that the Platelet-Activating Factor Receptor (PAFR) engagement in murine macrophages and dendritic cells (DCs) promotes a tolerogenic phenotype reversed by PAFR-antagonists treatment in vitro. Here, we investigated whether a PAFR antagonist would modulate the immune response in vivo. Mice were subcutaneously injected with OVA or OVA with PAFR-antagonist WEB2170 on days 0 and 7. On day 14, OVA–specific IgG2a and IgG1 were measured in the serum. The presence of WEB2170 during immunization significantly increased IgG2a without affecting IgG1 levels. When WEB2170 was added to OVA in complete Freund’s adjuvant, enhanced IgG2a but not IgG1 production was also observed, and CD4+ FoxP3+ T cell frequency in the spleen was reduced compared to mice immunized without the antagonist. Similar results were observed in PAFR-deficient mice, along with increased Tbet mRNA expression in the spleen. Additionally, bone marrow-derived DCs loaded with OVA were transferred into naïve mice and their splenocytes were co-cultured with fresh OVA-loaded DCs. CD4+ T cell proliferation was higher in the group transferred with DCs treated with the PAFR-antagonist. We propose that the activation of PAFR by ligands present in the site of immunization is able to fine-tune the adaptive immune response. PMID:27966635

  15. Zebrafish phenotypic screen identifies novel Notch antagonists.

    PubMed

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  16. Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.

    PubMed

    Duarte, E P; Oliveira, C R; Carvalho, A P

    1988-03-01

    The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of

  17. From Bioinactive ACTH to ACTH Antagonist: The Clinical Perspective

    PubMed Central

    Ghaddhab, Chiraz; Vuissoz, Jean-Marc; Deladoëy, Johnny

    2017-01-01

    The adrenocorticotropic hormone (ACTH) is a pituitary hormone derived from a larger peptide, the proopiomelanocortin (POMC), as are the MSHs (α-MSH, β-MSH, and γ-MSH) and the β-LPH-related polypeptides (Figure 1A). ACTH drives adrenal steroidogenesis and growth of the adrenal gland. ACTH is a 39 amino acid polypeptide that binds and activates its cognate receptor [melanocortin receptor 2 (MC2R)] through the two regions H6F7R8W9 and K15K16R17R18P19. Most POMC-derived polypeptides contain the H6F7R8W9 sequence that is conserved through evolution. This explains the difficulties in developing selective agonists or antagonists to the MCRs. In this review, we will discuss the clinical aspects of the role of ACTH in physiology and disease, and potential clinical use of selective ACTH antagonists. PMID:28228747

  18. Non-imidazole histamine NO-donor H3-antagonists.

    PubMed

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2005-01-01

    Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.

  19. Pharmacophore generation, atom-based 3D-QSAR, HQSAR and activity cliff analyses of benzothiazine and deazaxanthine derivatives as dual A2A antagonists/MAO‑B inhibitors.

    PubMed

    Bhayye, S S; Roy, K; Saha, A

    2016-02-12

    Dual inhibition of A2A and MAO-B is an emerging strategy in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) and hologram quantitative structure-activity relationship (HQSAR) models were generated with benzothiazine and deazaxanthine derivatives. Based on activity against A2A and MAO-B, two statistically significant 3D-QSAR models (r(2) = 0.96, q(2) = 0.76 and r(2) = 0.91, q(2) = 0.63) and HQSAR models (r(2) = 0.93, q(2) = 0.68 and r(2) = 0.97, q(2) = 0.58) were developed. In an activity cliff analysis, structural outliers were identified by calculating the Mahalanobis distance for a pair of compounds with A2A and MAO-B inhibitory activities. The generated 3D-QSAR and HQSAR models, activity cliff analysis, molecular docking and dynamic studies for dual target protein inhibitors provide key structural scaffolds that serve as building blocks in designing drug-like molecules for neurodegenerative diseases.

  20. Human glucagon receptor antagonists based on alkylidene hydrazides.

    PubMed

    Ling, Anthony; Plewe, Michael; Gonzalez, Javier; Madsen, Peter; Sams, Christian K; Lau, Jesper; Gregor, Vlad; Murphy, Doug; Teston, Kimberly; Kuki, Atsuo; Shi, Shenghua; Truesdale, Larry; Kiel, Dan; May, John; Lakis, James; Anderes, Kenna; Iatsimirskaia, Eugenia; Sidelmann, Ulla G; Knudsen, Lotte B; Brand, Christian L; Polinsky, Alex

    2002-02-25

    A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.

  1. Opioid antagonists for smoking cessation

    PubMed Central

    David, Sean P; Lancaster, Tim; Stead, Lindsay F; Evins, A. Eden; Prochaska, Judith J

    2014-01-01

    Background The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. Objectives To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. Search methods We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. Selection criteria We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. Data collection and analysis We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel

  2. Mineralcorticoid antagonists in heart failure.

    PubMed

    D'Elia, Emilia; Krum, Henry

    2014-10-01

    Mineralocorticoid receptor antagonists (MRAs) have become mandated therapy in patients with reduced ejection fraction (systolic) heart failure (HF) across all symptom classes. These agents should also be prescribed in the early post-myocardial infarction setting in those with reduced ejection fraction and either HF symptoms or diabetes. This article explores the pathophysiological role of aldosterone, an endogenous ligand for the mineralcorticoid receptor (MR), and summarizes the clinical data supporting guideline recommendations for these agents in systolic HF. The use of MRAs in novel areas beyond systolic HF ejection is also explored. Finally, the current status of newer agents will be examined.

  3. NK-1 Antagonists and Itch.

    PubMed

    Ständer, Sonja; Luger, Thomas A

    2015-01-01

    Substance P (SP) is an important mediator of pro-inflammatory mechanisms in the skin. It targets multiple cells such as keratinocytes, mast cells, and fibroblasts which are involved in the cutaneous generation of pruritus. This suggests that SP is an interesting target for therapy. In fact, in recent case reports and case series, SP antagonists demonstrated a significant antipruritic effect in acute and chronic pruritus such as drug-induced pruritus, paraneoplastic pruritus, prurigo nodularis, cutaneous T-cell lymphoma, and brachioradial pruritus.

  4. Heterocyclic 1,7-disubstituted indole sulfonamides are potent and selective human EP3 receptor antagonists.

    PubMed

    Hategan, Georgeta; Polozov, Alexandre M; Zeller, Wayne; Cao, Hua; Mishra, Rama K; Kiselyov, Alex S; Ramirez, Jose; Halldorsdottir, Gudrún; Andrésson, Thornorkell; Gurney, Mark E; Singh, Jasbir

    2009-12-01

    We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.

  5. Vitamin K antagonists: beyond bleeding.

    PubMed

    Krüger, Thilo; Floege, Jürgen

    2014-01-01

    Warfarin is the most widely used oral anticoagulant in clinical use today. Indications range from prosthetic valve replacement to recurrent thromboembolic events due to antiphospholipid syndrome. In hemodialysis (HD) patients, warfarin use is even more frequent than in the nonrenal population due to increased cardiovascular comorbidities. The use of warfarin in dialysis patients with atrial fibrillation requires particular caution because side effects may outweigh the assumed benefit of reduced stroke rates. Besides increased bleeding risk, coumarins exert side effects which are not in the focus of clinical routine, yet they deserve special consideration in dialysis patients and should influence the decision of whether or not to prescribe vitamin K antagonists in cases lacking clear guidelines. Issues to be taken into consideration in HD patients are the induction or acceleration of cardiovascular calcifications, a 10-fold increased risk of calciphylaxis and problems related to maintaining a target INR range. New anticoagulants like direct thrombin inhibitors are promising but have not yet been approved for ESRD patients. Here, we summarize the nontraditional side effects of coumarins and give recommendations about the use of vitamin K antagonists in ESRD patients.

  6. Cholinergic antagonists in a solitary wasp venom.

    PubMed

    Piek, T; Mantel, P

    1986-01-01

    The venom of the solitary wasp Philanthus triangulum contains a cholinergic antagonist of the nicotinic receptor of the rectus abdominis muscle of the frog, Xenopus laevis. The venom of African P. triangulum contains two different cholinergic factors, a competitive and a non-competitive antagonist. The venom of the European P. triangulum may not contain a competitive antagonist of the nicotinic receptor of X. laevis, but only a very strong non-competitive antagonist. The possible non-synonymity of both groups of P. triangulum is discussed.

  7. Antagonistic Coevolution of Marine Planktonic Viruses and Their Hosts

    NASA Astrophysics Data System (ADS)

    Martiny, Jennifer B. H.; Riemann, Lasse; Marston, Marcia F.; Middelboe, Mathias

    2014-01-01

    The potential for antagonistic coevolution between marine viruses and their (primarily bacterial) hosts is well documented, but our understanding of the consequences of this rapid evolution is in its infancy. Acquisition of resistance against co-occurring viruses and the subsequent evolution of virus host range in response have implications for bacterial mortality rates as well as for community composition and diversity. Drawing on examples from a range of environments, we consider the potential dynamics, underlying genetic mechanisms and fitness costs, and ecological impacts of virus-host coevolution in marine waters. Given that much of our knowledge is derived from laboratory experiments, we also discuss potential challenges and approaches in scaling up to diverse, complex networks of virus-host interactions. Finally, we note that a variety of novel approaches for characterizing virus-host interactions offer new hope for a mechanistic understanding of antagonistic coevolution in marine plankton.

  8. Antagonistic coevolution of marine planktonic viruses and their hosts.

    PubMed

    Martiny, Jennifer B H; Riemann, Lasse; Marston, Marcia F; Middelboe, Mathias

    2014-01-01

    The potential for antagonistic coevolution between marine viruses and their (primarily bacterial) hosts is well documented, but our understanding of the consequences of this rapid evolution is in its infancy. Acquisition of resistance against co-occurring viruses and the subsequent evolution of virus host range in response have implications for bacterial mortality rates as well as for community composition and diversity. Drawing on examples from a range of environments, we consider the potential dynamics, underlying genetic mechanisms and fitness costs, and ecological impacts of virus-host coevolution in marine waters. Given that much of our knowledge is derived from laboratory experiments, we also discuss potential challenges and approaches in scaling up to diverse, complex networks of virus-host interactions. Finally, we note that a variety of novel approaches for characterizing virus-host interactions offer new hope for a mechanistic understanding of antagonistic coevolution in marine plankton.

  9. A new alcohol antagonist: Phaclofen

    SciTech Connect

    Allan, A.M. ); Harris, R.A. )

    1989-01-01

    The ability of the GABA{sub B} receptor antagonist, phaclofen to alter behavioral effects of ethanol was evaluated by loss of righting reflex (sleep time), motor incoordination (bar holding), spontaneous locomotion (open field activity) and hypothermia. Pretreatment with phaclofen significantly decreased the effects of ethanol on motor incoordination, locomotor activity and hypothermia. However, phaclofen had no effect on either pentobarbital- or diazepam-induced motor incoordination. Phaclofen slightly increased the ED{sub 50} for loss of the righting reflex but did not alter either the duration of reflex loss produced by ethanol or blood ethanol levels at awakening. Our results suggest phaclofen is rapidly inactivated resulting in difficulty in observing antagonism of long duration ethanol effects. These findings suggest that the GABA{sub B} system may play a role in mediating several important actions of ethanol.

  10. Client Perceptions of Two Antagonist Programs.

    ERIC Educational Resources Information Center

    Capone, Thomas A.; And Others

    1980-01-01

    Reports results of a questionnaire administered to participants in an antagonist drug outpatient clinic and an antagonist drug work-release program to obtain awareness of acceptance of the program participants. Naltrexone patients recommended an alternative method of administering the drug and changing the money system to award deserving inmates…

  11. Antagonistic neural networks underlying differentiated leadership roles

    PubMed Central

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  12. Antianginal Actions of Beta-Adrenoceptor Antagonists

    PubMed Central

    2007-01-01

    Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of β-adrenoceptor antagonists as it relates to the treatment of angina. The β-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to β1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, β-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac β1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of β-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents. PMID:17998992

  13. Antagonistic coevolution accelerates molecular evolution

    PubMed Central

    Paterson, Steve; Vogwill, Tom; Buckling, Angus; Benmayor, Rebecca; Spiers, Andrew J.; Thomson, Nicholas R.; Quail, Mike; Smith, Frances; Walker, Danielle; Libberton, Ben; Fenton, Andrew; Hall, Neil; Brockhurst, Michael A.

    2013-01-01

    The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation1–3. Although the divergence observed at some host-resistance4–6 and parasite-infectivity7–9 genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Φ2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species. PMID:20182425

  14. Does intergenerational social mobility affect antagonistic attitudes towards ethnic minorities?

    PubMed

    Tolsma, Jochem; de Graaf, Nan Dirk; Quillian, Lincoln

    2009-06-01

    Up till now, no study satisfactorily addressed the effect of social mobility on antagonistic attitudes toward ethnic minorities. In this contribution, we investigate the effect of educational and class intergenerational mobility on ethnic stereotypes, ethnic threat, and opposition to ethnic intermarriage by using diagonal mobility models. We test several hypotheses derived from ethnic competition theory and socialization theory with data from the Social and Cultural Developments in The Netherlands surveys (SOCON, waves 1995, 2000, and 2005) and The Netherlands Kinship and Panel Study (NKPS, wave 2002). We find that the relative influence of social origin and social destination depends on the specific origin and destination combination. If one moves to a more tolerant social destination position, the influence of the social origin position is negligible. If on the other hand, one is socially mobile to a less tolerant social position, the impact of the origin on antagonistic attitudes is substantial and may even exceed the impact of the destination category. This confirms our hypothesis that adaptation to more tolerant norms is easier than adaptation to less tolerant norms. We find only meagre evidence for the hypothesis that downward mobility leads to frustration and consequently to more antagonistic attitudes.

  15. Antagonists of the kappa opioid receptor.

    PubMed

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  16. Emerging cardiovascular indications of mineralocorticoid receptor antagonists.

    PubMed

    Parviz, Yasir; Iqbal, Javaid; Pitt, Bertram; Adlam, David; Al-Mohammad, Abdallah; Zannad, Faiez

    2015-04-01

    Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.

  17. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks.

  18. The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

    NASA Astrophysics Data System (ADS)

    van Drooge, Marc J.; Donné-op den Kelder, Gabriëlle M.; Timmerman, Hendrik

    1991-08-01

    The active conformation of several histamine H1-antagonists is investigated. As a template molecule we used the antagonist cyproheptadine, which consists of a piperidylene ring connected to a tricyclic system. The piperidylene moiety is shown to be flexible. The global minimum is a chair conformation but, additionally, a second chair and various boat conformations have to be considered, as their energies are less than 5 kcal/mol above the energy of the global minimum. Two semi-rigid histamine H1-antagonists, phenindamine and triprolidine, were fitted onto the various conformations of cyproheptadine in order to derive the pharmacologically active conformation of cyproheptadine. At the same time, the active conformation of both phenindamine and triprolidine was derived. It is demonstrated that, within the receptor-bound conformation of cyproheptadine, the piperidylene ring most probably exists in a boat form.

  19. Macrophages: micromanagers of antagonistic signaling nanoclusters.

    PubMed

    Eggeling, Christian; Davis, Simon J

    2017-04-03

    How cells integrate antagonistic receptor signaling events is enigmatic. Using superresolution optical microscopy, Lopes et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608094) demonstrate the nanometer-scale molecular reorganization of antagonistic signaling receptors in macrophages, after engagement by the receptors of activating and inhibitory ligands. They propose that large-scale rearrangements of this type underpin decision-making by these cells.

  20. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.

    PubMed

    Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; Lażewska, Dorota; Adem, Abdu; Kieć-Kononowicz, Katarzyna

    2014-06-01

    To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.

  1. Carbobenzoxy amino acids: Structural requirements for cholecystokinin receptor antagonist activity

    SciTech Connect

    Maton, P.N.; Sutliff, V.E.; Jensen, R.T.; Gardner, J.D.

    1985-04-01

    The authors used dispersed acini prepared from guinea pig pancreas to examine 28 carbobenzoxy (CBZ) amino acids for their abilities to function as cholecystokinin receptor antagonists. All amino acid derivatives tested, except for CBZ-alanine, CBZ-glycine, and N alpha-CBZ- lysine, were able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, there was a good correlation between the ability of a carbobenzoxy amino acid to inhibit stimulated amylase secretion and the ability of the amino acid derivative to inhibit binding of /sup 125/I-cholecystokinin. The inhibition of cholecystokinin-stimulated amylase secretion was competitive, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor. The potencies with which the various carbobenzoxy amino acids inhibited the action of cholecystokinin varied 100-fold and CBZ-cystine was the most potent cholecystokinin receptor antagonist. This variation in potency was primarily but not exclusively a function of the hydrophobicity of the amino acid side chain.

  2. Calcium antagonists and atherosclerosis protection in hypertension.

    PubMed

    Hernández, Rafael Hernández; Armas-Hernández, María José; Velasco, Manuel; Israili, Zafar H; Armas-Padilla, María Cristina

    2003-01-01

    Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima

  3. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists.

    PubMed

    Hernandez, E R

    2000-06-01

    When gonadotrophin-releasing hormone (GnRH) was discovered, the agonist and antagonist of GnRH were developed to control the release of FSH and LH by the gonadotrophs. More than 10 years of research were needed to develop a GnRH antagonist free of histamine release. Recent studies have shown that these GnRH antagonists are effective in preventing a rise in LH during ovarian stimulation in IVF. However, a decrease in ongoing pregnancies seems to suggest that implantation rates per transferred embryo are reduced in GnRH antagonist-stimulated cycles. In my opinion, these data highlight an area less well known to clinicians: the role of the GnRH antagonist at the cellular level in extrapituitary tissues. There are sufficient data in the literature suggesting that GnRH antagonist is an inhibitor of the cell cycle by decreasing the synthesis of growth factors. Given that, for folliculogenesis, blastomere formation and endometrium development, mitosis is everything; the interaction between the GnRH antagonist and the GnRH receptor (present in all these cells and tissues) may compromise the mitotic programme of these cells. This is the Rubicon for the GnRH antagonist: to demonstrate irrevocably that, at the minimal doses necessary to suppress LH release, it does not affect processes such as implantation, embryo development and folliculogenesis.

  4. Discovery of novel dihydrobenzofuran cyclopropane carboxylic acid based calcium sensing receptor antagonists for the treatment of osteoporosis.

    PubMed

    Liang, Gui-Bai; Zhou, Changyou; Huo, Xianghong; Wang, Hank; Yang, Xuelin; Huang, Shaoqiang; Wang, Haisheng; Wilkinson, Hilary; Luo, Lusong; Tang, Wei; Sutton, David; Li, Hong; Zaller, Dennis; Meinke, Peter T

    2016-08-15

    In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.

  5. Chemical communication in scarab beetles: reciprocal behavioral agonist-antagonist activities of chiral pheromones.

    PubMed Central

    Leal, W S

    1996-01-01

    A novel mechanism of reciprocal behavioral agonist-antagonist activities of enantiomeric pheromones plays a pivotal role in overcoming the signal-to-noise problem derived from the use of a single-constituent pheromone system in scarab beetles. Female Anomala osakana produce (S, Z)-5-(+)-(1-decenyl)oxacyclopentan-2-one, which is highly attractive to males; the response is completely inhibited even by 5% of its antipode. These two enantiomers have reverse roles in the Popillia japonica sex pheromone system. Chiral GC-electroantennographic detector experiments suggest that A. osakana and P. japonica have both R and S receptors that are responsible for behavioral agonist and antagonist responses. PMID:8901541

  6. Unprecedented NES non-antagonistic inhibitor for nuclear export of Rev from Sida cordifolia.

    PubMed

    Tamura, Satoru; Kaneko, Masafumi; Shiomi, Atsushi; Yang, Guang-Ming; Yamaura, Toshiaki; Murakami, Nobutoshi

    2010-03-15

    Bioassay-guided separation from the MeOH extract of the South American medicinal plant Sida cordifolia resulted in isolation of (10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (1) as an unprecedented NES non-antagonistic inhibitor for nuclear export of Rev. This mechanism of action was established by competitive experiment by the biotinylated probe derived from leptomycin B, the known NES antagonistic inhibitor. Additionally, structure-activity relationship analysis by use of the synthesized analogs clarified cooperation of several functionalities in the Rev-export inhibitory activity of 1.

  7. Pharmacological analysis of CCK2 receptor antagonists using isolated rat stomach ECL cells

    PubMed Central

    Lindström, Erik; Björkqvist, Maria; Håkanson, Rolf

    1999-01-01

    Gastrin stimulates rat stomach ECL cells to secrete histamine and pacreastatin, a chromogranin A (CGA)-derived peptide. The present report describes the effect of nine cholecystokinin2 (CCK2) receptor antagonists and one CCK1 receptor antagonist on the gastrin-evoked secretion of pancreastatin from isolated ECL cells.The CCK2 receptor antagonists comprised three benzodiazepine derivatives L-740,093, YM022 and YF476, one ureidoacetamide compound RP73870, one benzimidazole compound JB 93182, one ureidoindoline compound AG041R and three tryptophan dipeptoids PD 134308 (CI988), PD135158 and PD 136450. The CCK1 receptor antagonist was devazepide.A preparation of well-functioning ECL cells (∼80% purity) was prepared from rat oxyntic mucosa using counter-flow elutriation. The cells were cultured for 48 h in the presence of 0.1 nM gastrin; they were then washed and incubated with antagonist alone or with various concentrations of antagonist plus 10 nM gastrin (a maximally effective concentration) for 30 min. Gastrin dose-response curves were constructed in the absence or presence of increasing concentrations of antagonist. The amount of pancreastatin secreted was determined by radioimmunoassay.The gastrin-evoked secretion of pancreastatin was inhibited in a dose-dependent manner. YM022, AG041R and YF476 had IC50 values of 0.5, 2.2 and 2.7 nM respectively. L-740,093, JB93182 and RP73870 had IC50 values of 7.8, 9.3 and 9.8 nM, while PD135158, PD136450 and PD134308 had IC50 values of 76, 135 and 145 nM. The CCK1 receptor antagonist devazepide was a poor CCK2 receptor antagonist with an IC50 of about 800 nM.YM022, YF476 and AG041R were chosen for further analysis. YM022 and YF476 shifted the gastrin dose-response curve to the right in a manner suggesting competitive antagonism, while the effects of AG041R could not be explained by simple competitive antagonism. pKB values were 11.3 for YM022, 10.8 for YF476 and the apparent pKB for AG041R was 10.4. PMID

  8. Functions of 5-HT2A receptor and its antagonists in the cardiovascular system.

    PubMed

    Nagatomo, Takafumi; Rashid, Mamunur; Abul Muntasir, Habib; Komiyama, Tadazumi

    2004-10-01

    The serotonin (5-hydroxytryptamine, 5-HT) receptors have conventionally been divided into seven subfamilies, most of which have several subtypes. Among them, 5-HT(2A) receptor is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Accordingly, selective 5-HT(2A) antagonists may have potential in the treatment of cardiovascular diseases. Sarpogrelate, a selective 5-HT(2A) antagonist, has been introduced clinically as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis. Molecular modeling studies also suggest that sarpogrelate is a 5-HT(2A) selective antagonist and is likely to have pharmacological effects beneficial in the treatment of cardiovascular diseases. This review describes the above findings as well as the signaling linkages of the 5-HT(2A) receptors and the mode of agonist binding to 5-HT(2A) receptor using data derived from molecular modeling and site-directed mutagenesis.

  9. Development of selective agonists and antagonists of P2Y receptors

    PubMed Central

    Ivanov, Andrei A.; de Castro, Sonia; Harden, T. Kendall; Ko, Hyojin

    2008-01-01

    Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y1, P2Y2, and P2Y6 receptors and nucleotide antagonists selective for P2Y1 and P2Y12 receptors are now known. Selective nonnucleotide antagonists were reported for P2Y1, P2Y2, P2Y6, P2Y11, P2Y12, and P2Y13 receptors. At the P2Y1 and P2Y12 receptors, nucleotide agonists (5′-diphosphate derivatives) were converted into antagonists of nanomolar affinity by altering the phosphate moieties, with a focus particularly on the ribose conformation and substitution pattern. Nucleotide analogues with conformationally constrained ribose-like rings were introduced as selective receptor probes for P2Y1 and P2Y6 receptors. Screening chemically diverse compound libraries has begun to yield new lead compounds for the development of P2Y receptor antagonists, such as competitive P2Y12 receptor antagonists with antithrombotic activity. Selective agonists for the P2Y4, P2Y11, and P2Y13 receptors and selective antagonists for P2Y4 and P2Y14 receptors have not yet been identified. The P2Y14 receptor appears to be the most restrictive of the class with respect to modification of the nucleobase, ribose, and phosphate moieties. The continuing process of ligand design for the P2Y receptors will aid in the identification of new clinical targets. PMID:18600475

  10. Topical interleukin-1 receptor antagonist inhibits inflammatory cell infiltration into the cornea.

    PubMed

    Stapleton, W Michael; Chaurasia, Shyam S; Medeiros, Fabricio W; Mohan, Rajiv R; Sinha, Sunilima; Wilson, Steven E

    2008-05-01

    Interleukin (IL)-1alpha and beta are important modulators of many functions of corneal epithelial and stromal cells that occur following injury to the cornea, including the influx of bone marrow-derived inflammatory cells into the stroma attracted by chemokines released from the stroma and epithelium. In this study, we examined the effect of topical soluble IL-1 receptor antagonist on bone marrow-derived cell influx following corneal epithelial scrape injury in a mouse model. C57BL/6 mice underwent corneal epithelial scrape followed by application of IL-1 receptor antagonist (Amgen, Thousand Oaks, CA) at a concentration of 20 mg/ml or vehicle for 24 h prior to immunocytochemical detection of marker CD11b-positive cells into the stroma. In two experiments, topical IL-1 receptor antagonist had a marked effect in blocking cell influx. For example, in experiment 1, topical IL-1 receptor antagonist markedly reduced detectible CD11b-positive cells into the corneal stroma at 24h after epithelial injury compared with the vehicle control (3.5+/-0.5 (standard error of the mean) cells/400x field and 13.9+/-1.2 cells/400x field, respectively, p<0.01). A second experiment with a different observer performing cell counting had the same result. Thus, the data demonstrate conclusively that topical IL-1 receptor antagonist markedly down-regulates CD-11b-positive monocytic cell appearance in the corneal stroma. Topical IL-1 receptor antagonist could be an effective adjuvant for clinical treatment of corneal conditions in which unwanted inflammation has a role in the pathophysiology of the disorder.

  11. Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents.

    PubMed

    Tsutsumi, Hiroshi; Tanaka, Tomohiro; Ohashi, Nami; Masuno, Hiroyuki; Tamamura, Hirokazu; Hiramatsu, Kenichi; Araki, Takanobu; Ueda, Satoshi; Oishi, Shinya; Fujii, Nobutaka

    2007-01-01

    The chemokine receptor CXCR4 possesses multiple critical functions in normal and pathologic physiology. CXCR4 is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1). The interaction between CXCL12 and CXCR4 plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, and so on. This interaction is also known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA), and pulmonary fibrosis. It is conjectured that this interaction may be a critical therapeutic target in all of these diseases, and several CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogues, were previously developed in our laboratory as specific CXCR4 antagonists that were identified as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents, and anti-RA agents. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were also previously found as CXCR4 antagonist leads based on pharmacophores of T140. This review article describes the elucidation of multiple functions of CXCR4 antagonists and the development of a number of low-molecular weight CXCR4 antagonists involving FC131 analogues and other compounds with different scaffolds including linear-type structures.

  12. The evolution of histamine H₃ antagonists/inverse agonists.

    PubMed

    Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

    2011-01-01

    This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

  13. Quinidine as a muscarinic antagonist: a structural approach.

    PubMed

    Ciechanowicz-Rutkowska, M; Oleksyn, B J; Suszko-Purzycka, A; Lipińska, T

    1992-06-01

    The synthesis, spectroscopic characteristics, and single-crystal X-ray structural analysis of quitenidine methyl ester monohydrate, a derivative of the muscarinic antagonist quinidine, are presented. Quitenidine methyl ester monohydrate (C20H24N2O4.H2O) crystallizes in the orthorhombic space group P2(1)2(1)2(1), with a = 16.69(3) A, b = 12.46(2) A, c = 9.70(1) A, and Z = 4. The crystal structure was refined to a discrepancy factor (R) of 0.097. Substitution of the quinidine vinyl chain with a carboxymethyl group does not influence the conformation. The carboxymethyl group is positionally disordered, a fact that complicates refinement of the structure. The water molecule is bonded to the quinuclidine nitrogen atom, and the hydroxyl group forms an intermolecular hydrogen bond with the quinoline nitrogen atom. The molecular structure of the ester was compared with those of quinidine, quinine, and four other antimuscarinic agents. An approximately linear relationship between the distance from the nonaromatic nitrogen to the plane of the aromatic part of the molecules and the blocking potency of these agents was noted; the greater this distance, the more potent is the antagonist.

  14. Antagonist-Elicited Cannabis Withdrawal in Humans

    PubMed Central

    Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A.

    2013-01-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ9-tetrahydrocannabinol (THC) dosages (40–120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0–8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. PMID:21869692

  15. Antagonistic and synergistic interactions among predators.

    PubMed

    Huxel, Gary R

    2007-08-01

    The structure and dynamics of food webs are largely dependent upon interactions among consumers and their resources. However, interspecific interactions such as intraguild predation and interference competition can also play a significant role in the stability of communities. The role of antagonistic/synergistic interactions among predators has been largely ignored in food web theory. These mechanisms influence predation rates, which is one of the key factors regulating food web structure and dynamics, thus ignoring them can potentially limit understanding of food webs. Using nonlinear models, it is shown that critical aspects of multiple predator food web dynamics are antagonistic/synergistic interactions among predators. The influence of antagonistic/synergistic interactions on coexistence of predators depended largely upon the parameter set used and the degree of feeding niche differentiation. In all cases when there was no effect of antagonism or synergism (a ( ij )=1.00), the predators coexisted. Using the stable parameter set, coexistence occurred across the range of antagonism/synergism used. However, using the chaotic parameter strong antagonism resulted in the extinction of one or both species, while strong synergism tended to coexistence. Whereas using the limit cycle parameter set, coexistence was strongly dependent on the degree of feeding niche overlap. Additionally increasing the degree of feeding specialization of the predators on the two prey species increased the amount of parameter space in which coexistence of the two predators occurred. Bifurcation analyses supported the general pattern of increased stability when the predator interaction was synergistic and decreased stability when it was antagonistic. Thus, synergistic interactions should be more common than antagonistic interactions in ecological systems.

  16. Antagonist-elicited cannabis withdrawal in humans.

    PubMed

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2011-10-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

  17. Progress in corticotropin-releasing factor-1 antagonist development

    PubMed Central

    Zorrilla, Eric P.; Koob, George F.

    2010-01-01

    Corticotropin-releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence suggests the limited efficacy of CRF1 antagonists as antidepressants, CRF1 antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand–receptor interactions for CRF family receptors might yield chemically novel CRF1 receptor antagonists, including peptide CRF1 antagonists, antagonists with signal transduction selectivity and nonpeptide CRF1 antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF1 antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome. PMID:20206287

  18. [N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties.

    PubMed

    Marczak, Ewa D; Jinsmaa, Yunden; Li, Tingyou; Bryant, Sharon D; Tsuda, Yuko; Okada, Yoshio; Lazarus, Lawrence H

    2007-10-01

    [N-allyl-Dmt1]-endomorphin-1 and -2 ([N-allyl-Dmt1]-EM-1 and -2) are new selective micro-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2',6'-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5'-O-(3-[35S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-allyl-Dmt1]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine- and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone- and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.

  19. Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists

    PubMed Central

    Appendino, Giovanni; Harrison, Selena; De Petrocellis, Luciano; Daddario, Nives; Bianchi, Federica; Schiano Moriello, Aniello; Trevisani, Marcello; Benvenuti, Francesca; Geppetti, Pierangelo; Di Marzo, Vincenzo

    2003-01-01

    The C-5 halogenation of the vanillyl moiety of resiniferatoxin, an ultrapotent agonist of vanilloid TRPV1 receptors, results in a potent antagonist for these receptors. Here, we have synthesized a series of halogenated derivatives of ‘synthetic capsaicin' (nonanoyl vanillamide=nordihydrocapsaicin) differing for the nature (iodine, bromine–chlorine) and the regiochemistry (C-5, C-6) of the halogenation.The activity of these compounds was investigated on recombinant human TRPV1 receptors overexpressed in HEK-293 cells. None of the six compounds exerted any significant agonist activity, as assessed by measuring their effect on TRPV1-mediated calcium mobilization. Instead, all compounds antagonized, to various extents, the effect of capsaicin in this assay.All 6-halo-nordihydrocapsaicins behaved as competitive antagonists against human TRPV1 according to the corresponding Schild's plots, and were more potent than the corresponding 5-halogenated analogues. The iodo-derivatives were more potent than the bromo- and chloro-derivatives.Using human recombinant TRPV1, 6-iodo-nordihydrocapsaicin (IC50=10 nM against 100 nM capsaicin) was about four times more potent than the prototypical TRPV1 antagonist, capsazepine, and was tested against capsaicin also on native TRPV1 in: (i) rat dorsal root ganglion neurons in culture; (ii) guinea-pig urinary bladder; and (iii) guinea-pig bronchi. In all cases, except for the guinea-pig bronchi, the compound was significantly more potent than capsazepine as a TRPV1 antagonist.In conclusion, 6-iodo-nordihydrocapsaicin, a stable and easily prepared compound, is a potent TRPV1 antagonist and a convenient replacement for capsazepine in most of the in vitro preparations currently used to assess the activity of putative vanilloid receptor agonists. PMID:12922928

  20. Novel benzimidazole-based MCH R1 antagonists.

    PubMed

    Carpenter, Andrew J; Al-Barazanji, Kamal A; Barvian, Kevin K; Bishop, Michael J; Britt, Christy S; Cooper, Joel P; Goetz, Aaron S; Grizzle, Mary K; Hertzog, Donald L; Ignar, Diane M; Morgan, Ronda O; Peckham, Gregory E; Speake, Jason D; Swain, Will R

    2006-10-01

    The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

  1. Functionalized Congeners of P2Y1 Receptor Antagonists:

    SciTech Connect

    de Castro, Sonia; Maruoka, Hiroshi; Hong, Kunlun; Kilbey, II, S Michael; Costanzi, Stefano; Hechler, Béatrice; Gachet, Christian; Harden, T. Kendall; Jacobson, Kenneth A.

    2010-01-01

    The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to

  2. Synthesis of Novel Estrogen Receptor Antagonists Using Metal-Catalyzed Coupling Reactions and Characterization of Their Biological Activity

    PubMed Central

    Jiang, Xiang-Rong; Wang, Pan; Smith, Carolyn L.; Zhu, Bao Ting

    2013-01-01

    Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα, and showed that they could tightly bind to the ERα in a similar manner as ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with comparable ER affinity as ICI-182,780. PMID:23448346

  3. Development of Kappa Opioid Receptor Antagonists

    PubMed Central

    Carroll, F. Ivy; Carlezon, William A.

    2013-01-01

    Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness. PMID:23360448

  4. The treatment of hyponatraemia using vasopressin antagonists.

    PubMed

    Gross, P; Palm, C

    2000-03-01

    Hyponatraemia is a frequent electrolyte disorder. It is primarily attributable to vasopressin excess plus sustained fluid intake. Hyponatraemia causes CNS symptoms, especially during the first 2-4 days; these symptoms are related to brain swelling. Hyponatraemia occurs in the setting of liver cirrhosis and congestive cardiac failure, in which it is related to stimulation by low arterial blood pressure acting through baroreceptors. Hyponatraemia also occurs in the syndrome of inappropriate antidiuretic hormone secretion, usually from neoplasms releasing vasopressin. The conventional treatment of hyponatraemia used to be fluid restriction and treatment of the underlying disorder. This kind of treatment has been unreliable, cumbersome and difficult to comply with for the patient. In the future, effective vasopressin V2 antagonists will become available for clinical use in the treatment of hyponatraemia, and are expected to improve the management of hyponatraemia. Pharmacological characteristics and observations of biological effects of three antagonists are reported in the present article.

  5. TRPV1 antagonists as potential antitussive agents.

    PubMed

    McLeod, Robbie L; Correll, Craig C; Jia, Yanlin; Anthes, John C

    2008-01-01

    Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current

  6. Interactions of Freshwater Cyanobacteria with Bacterial Antagonists

    PubMed Central

    Beier, Sara; Grabherr, Manfred

    2017-01-01

    ABSTRACT Cyanobacterial and algal mass development, or blooms, have severe effects on freshwater and marine systems around the world. Many of these phototrophs produce a variety of potent toxins, contribute to oxygen depletion, and affect water quality in several ways. Coexisting antagonists, such as cyanolytic bacteria, hold the potential to suppress, or even terminate, such blooms, yet the nature of this interaction is not well studied. We isolated 31 cyanolytic bacteria affiliated with the genera Pseudomonas, Stenotrophomonas, Acinetobacter, and Delftia from three eutrophic freshwater lakes in Sweden and selected four phylogenetically diverse bacterial strains with strong-to-moderate lytic activity. To characterize their functional responses to the presence of cyanobacteria, we performed RNA sequencing (RNA-Seq) experiments on coculture incubations, with an initial predator-prey ratio of 1:1. Genes involved in central cellular pathways, stress-related heat or cold shock proteins, and antitoxin genes were highly expressed in both heterotrophs and cyanobacteria. Heterotrophs in coculture expressed genes involved in cell motility, signal transduction, and putative lytic activity. l,d-Transpeptidase was the only significantly upregulated lytic gene in Stenotrophomonas rhizophila EK20. Heterotrophs also shifted their central metabolism from the tricarboxylic acid cycle to the glyoxylate shunt. Concurrently, cyanobacteria clearly show contrasting antagonistic interactions with the four tested heterotrophic strains, which is also reflected in the physical attachment to their cells. In conclusion, antagonistic interactions with cyanobacteria were initiated within 24 h, and expression profiles suggest varied responses for the different cyanobacteria and studied cyanolytes. IMPORTANCE Here, we present how gene expression profiles can be used to reveal interactions between bloom-forming freshwater cyanobacteria and antagonistic heterotrophic bacteria. Species

  7. Medicinal chemistry of competitive kainate receptor antagonists.

    PubMed

    Larsen, Ann M; Bunch, Lennart

    2011-02-16

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field.

  8. Medicinal Chemistry of Competitive Kainate Receptor Antagonists

    PubMed Central

    2010-01-01

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1−5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure−activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  9. NMDA Receptor Antagonists for Treatment of Depression

    PubMed Central

    Ates-Alagoz, Zeynep; Adejare, Adeboye

    2013-01-01

    Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery. PMID:24276119

  10. Pharmacological analysis of calcium antagonist receptors

    SciTech Connect

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)(/sup 3/H)desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) (/sup 3/H)desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor.

  11. Identification of a GPER/GPR30 Antagonist with Improved Estrogen Receptor Counterselectivity

    PubMed Central

    Dennis, Megan K.; Field, Angela S.; Burai, Ritwik; Ramesh, Chinnasamy; Petrie, Whitney K.; Bologa, Cristian G.; Oprea, Tudor I.; Yamaguchi, Yuri; Hayashi, Shin-ichi; Sklar, S. Larry A.; Hathaway, Helen J.; Arterburn, Jeffrey B.; Prossnitz, Eric R.

    2011-01-01

    GPER/GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates many aspects of mammalian biology and physiology. We have previously described both a GPER-selective agonist G-1 and antagonist G15 based on a tetrahydro-3H-cyclopenta[c]quinoline scaffold. The antagonist lacks an ethanone moiety that likely forms important hydrogen bonds involved in receptor activation. Computational docking studies suggested that the lack of the ethanone substituent in G15 could minimize key steric conflicts, present in G-1, that limit binding within the ERα ligand binding pocket. In this report, we identify low-affinity cross-reactivity of the GPER antagonist G15 to the classical estrogen receptor ERα. To generate an antagonist with enhanced selectivity, we therefore synthesized an isosteric G-1 derivative, G36, containing an isopropyl moiety in place of the ethanone moiety. We demonstrate that G36 shows decreased binding and activation of ERα, while maintaining its antagonist profile towards GPER. G36 selectively inhibits estrogen-mediated activation of PI3K by GPER but not ERα. It also inhibits estrogen- and G-1-mediated calcium mobilization as well as ERK1/2 activation, with no effect on EGF-mediated ERK1/2 activation. Similar to G15, G36 inhibits estrogen- and G-1-stimulated proliferation of uterine epithelial cells in vivo. The identification of G36 as a GPER antagonist with improved ER counterselectivity represents a significant step towards the development of new highly selective therapeutics for cancer and other diseases. PMID:21782022

  12. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  13. Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies.

    PubMed

    Nagase, Hiroshi; Yamamoto, Naoshi; Yata, Masahiro; Ohrui, Sayaka; Okada, Takahiro; Saitoh, Tsuyoshi; Kutsumura, Noriki; Nagumo, Yasuyuki; Irukayama-Tomobe, Yoko; Ishikawa, Yukiko; Ogawa, Yasuhiro; Hirayama, Shigeto; Kuroda, Daisuke; Watanabe, Yurie; Gouda, Hiroaki; Yanagisawa, Masashi

    2017-02-09

    Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.

  14. 1,7-Disubstituted oxyindoles are potent and selective EP(3) receptor antagonists.

    PubMed

    Zhou, Nian; Polozov, Alexandre M; O'Connell, Matthew; Burgeson, James; Yu, Peng; Zeller, Wayne; Zhang, Jun; Onua, Emmanuel; Ramirez, Jose; Palsdottir, Gudrun A; Halldorsdottir, Gudrun V; Andresson, Thorkell; Kiselyov, Alex S; Gurney, Mark; Singh, Jasbir

    2010-04-15

    A series of novel 1,7-disubstituted oxyindoles were shown to be potent and selective EP(3) receptor antagonists. Variation of substitution pattern at the C-3 position of indole enhanced in vitro metabolic stability of the resulting derivatives. Series 27a-c showed >1000-fold selectivity over a panel of prostanoid receptors including IP, FP, EP(1), EP(2) and EP(4). These agents also featured low CYP inhibition and good activity in the functional rat platelet aggregation assay.

  15. 2-Amino-4-arylthiazole compounds as TRPA1 antagonists (WO 2012085662): a patent evaluation.

    PubMed

    De Petrocellis, Luciano; Schiano Moriello, Aniello

    2013-01-01

    The patent claims 2-amino-4-arylthiazole derivative compounds as inhibitors of the TRPA1 (transient receptor potential ankyrin, member 1) receptor. These compounds are potent antagonists on the basis of the results of in vitro assays, and are expected to be useful for treating conditions and disorders associated with TRPA1 function such as pain, chronic pain, neuropathic pain, rheumatoid arthritic pain, osteoarthritic pain, diabetic neuropathy and inflammatory disorders.

  16. Recent Patents on Novel P2X7 Receptor Antagonists and Their Potential for Reducing Central Nervous System Inflammation

    PubMed Central

    Friedle, Scott A.; Curet, Marjorie A.; Watters, Jyoti J.

    2009-01-01

    Inflammation arises in the CNS from a number of neurodegenerative and oncogenic disorders, as well as from ischemic and traumatic brain injuries. These pathologies give rise to increased levels of extracellular adenine nucleotides which, via activation of a variety of cell surface P2 purinergic receptors, influence the inflammatory activities of responding immune cells. One P2 receptor subtype in particular, the P2X7 receptor, potentiates the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) from macrophage-like cells. It is also thought to contribute to secondary brain injury by inducing neuronal cell death. Therefore, antagonism of this receptor could have significant therapeutic impact on all disorders, not just CNS, to which excessive inflammatory activities contribute. The use of currently available P2X7 receptor antagonists for the treatment of CNS inflammation has been limited to the generally non-selective antagonists PPADS, oxidized ATP, Brilliant Blue G, suramin, calmidizolium, and KN-62. However, the recent patents and development of novel P2X7 receptor antagonists, as discussed in this review, will provide new tools both for clinical and research purposes. Here we discuss compounds for which patents have been applied since 2006, from the following categories: benzamide inhibitors, bicycloheteroaryl compounds, acylhdranzine antagonists, biaromatic P2X7 antagonists, heterocyclic compounds and amide derivatives, and aromatic amine antagonists. PMID:19705995

  17. Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists.

    PubMed

    Hamdi, Haïfa; Mariette, Xavier; Godot, Véronique; Weldingh, Karin; Hamid, Abdul Monem; Prejean, Maria-Victoria; Baron, Gabriel; Lemann, Marc; Puechal, Xavier; Breban, Maxime; Berenbaum, Francis; Delchier, Jean-Charles; Flipo, René-Marc; Dautzenberg, Bertrand; Salmon, Dominique; Humbert, Marc; Emilie, Dominique

    2006-01-01

    Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-gamma. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-gamma release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-gamma upon challenge with mycobacterial antigens. Added in vitro, they

  18. Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

    PubMed

    Skudlarek, Jason W; DiMarco, Christina N; Babaoglu, Kerim; Roecker, Anthony J; Bruno, Joseph G; Pausch, Mark A; O'Brien, Julie A; Cabalu, Tamara D; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L; Wuelfing, W Peter; Garson, Susan L; Fox, Steven V; Savitz, Alan T; Harrell, Charles M; Gotter, Anthony L; Winrow, Christopher J; Renger, John J; Kuduk, Scott D; Coleman, Paul J

    2017-03-15

    In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.

  19. 2-Aminothienopyridazines as Novel Adenosine A1 Receptor Allosteric Modulators and Antagonists

    PubMed Central

    Ferguson, Gemma N.; Valant, Celine; Horne, James; Figler, Heidi; Flynn, Bernard L.; Linden, Joel; Chalmers, David K.; Sexton, Patrick M.; Christopoulos, Arthur; Scammells, Peter J.

    2008-01-01

    A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tert-butylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A1 receptor (A1AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A1AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A1AR-mediated [35S]GTPγS binding and [3H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A1AR antagonists that can also recognize the receptor’s allosteric site with lower potency. PMID:18771255

  20. Exploratory studies on development of the chemokine receptor CXCR4 antagonists toward downsizing.

    PubMed

    Tamamura, Hirokazu; Tsutsumi, Hiroshi; Nomura, Wataru; Fujii, Nobutaka

    2008-02-10

    Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor-1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.

  1. Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.

    PubMed

    Balboni, Gianfranco; Salvadori, Severo; Trapella, Claudio; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Neumeyer, John L

    2010-02-17

    Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.

  2. Antagonistic functional duality of cancer genes.

    PubMed

    Stepanenko, A A; Vassetzky, Y S; Kavsan, V M

    2013-10-25

    Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene-chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and

  3. Neuromuscular adaptations following antagonist resisted training.

    PubMed

    MacKenzie, Sasho J; Rannelli, Luke A; Yurchevich, Jordan J

    2010-01-01

    The purpose was to assess a novel form of strength training, antagonist resisted training (ART), with potential use in microgravity and athletic rehabilitation settings. ART uses the force from antagonist muscles, during cocontractions, as the source of resistance for the agonists. Strength and electromyography (EMG) measurements were recorded before and after a 6-week training program during which participants trained the left arm while the right arm served as a control. Training was designed so that the elbow extensors (antagonists) served as resistance for the elbow flexors (agonists). Elbow flexor and extensor strengths were measured during maximal isometric contractions with the elbow fixed at 90 degrees. EMG was recorded from the biceps brachii and lateral head of the triceps brachii during all strength tests. EMG was also recorded from both muscles during a maximal isometric cocontraction of the elbow flexors and extensors. Elbow flexion strength increased significantly for the trained arm (5.8%) relative to the control (0.5%) (p = 0.003). Elbow extension strength of the trained limb also increased significantly (8.5%) relative to the control (4.5%) (p = 0.029). Biceps and triceps EMG, during maximum strength tests, increased significantly for the trained arm (18.5 and 18.6%) relative to the control (0.5 and -5.2%) (p = 0.035 and p = 0.01). Biceps and triceps EMG, during maximum cocontraction tests, increased significantly for the trained arm (30.1 and 61.1%) relative to the control (9.2 and 1.1%) (p = 0.042 and p = 0.0005). ART was found to increase strength and therefore could be an effective form of resistance training. Because it requires no equipment, ART may be especially applicable in microgravity environments, which have space and weight constraints.

  4. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  5. Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities.

    PubMed

    Berglund, Susanne; Egner, Bryan J; Gradén, Henrik; Gradén, Joakim; Morgan, David G A; Inghardt, Tord; Giordanetto, Fabrizio

    2009-08-01

    The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.

  6. Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

    PubMed Central

    Biswas, Arunima; Mani, Sridhar; Redinbo, Matthew R.; Krasowski, Matthew D.; Li, Hao; Ekins, Sean

    2010-01-01

    The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics. PMID:19415465

  7. New 1-arylindoles based serotonin 5-HT7 antagonists. Synthesis and binding evaluation studies.

    PubMed

    Sagnes, Charlène; Fournet, Guy; Satala, Grzegorz; Bojarski, Andrzej J; Joseph, Benoît

    2014-03-21

    Based on 5-HT1A and 5-HT7 ligand MR25003 scaffold, a new series of 1-aryl indole analogues were prepared and evaluated against 5-HT7 receptors. Modulations of aryl moieties provided a large number of new indolic derivatives. Most of compounds tested have displayed 5-HT7 affinity in the nanomolar range. Among them, 1-(naphthyl)indole derivative 3p (Ki (5-HT7) = 4.5 nM) showed also a good selectivity over 5-HT1A, 5-HT2A and 5-HT6 receptors. This compound was pharmacology characterized as an antagonist.

  8. Antioxidant effects of calcium antagonists in rat brain homogenates.

    PubMed

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  9. B-9972 (D-Arg-[Hyp3,Igl5,Oic7,Igl8]-bradykinin) is an inactivation-resistant agonist of the bradykinin B2 receptor derived from the peptide antagonist B-9430 (D-Arg-[Hyp3,Igl5,D-Igl7,Oic8]-bradykinin): pharmacologic profile and effective induction of receptor degradation.

    PubMed

    Bawolak, Marie-Thérèse; Gera, Lajos; Morissette, Guillaume; Stewart, John M; Marceau, François

    2007-11-01

    The bradykinin B(2) receptor is a heptahelical receptor regulated by a cycle of phosphorylation, endocytosis, and extensive recycling at the cell surface following agonist stimulation. B-9430 (d-Arg-[Hyp(3),Igl(5),D-Igl(7),Oic(8)]-bradykinin) is a second generation peptide antagonist found to be competitive at the human B(2) receptor and insurmountable at the rabbit B(2) receptor (contractility assays, isolated human umbilical and rabbit jugular veins). Two isomers of this peptide were prepared: B-10344 (D-Arg-[Hyp(3),Igl(5),Oic(7),D-Igl(8)]-bradykinin; inverted sequence Oic(7), D-Igl(8)) and B-9972 (D-Arg-[Hyp(3),Igl(5),Oic(7),Igl(8)]-bradykinin); they are low- and high-potency agonists, respectively, in vascular preparations. The potency gap between bradykinin and B-9972 is narrow in contractility assays, despite the fact that B-9972 affinity is 7-fold inferior at the rabbit B(2) receptor (radioligand binding competition assay). The effects of agonists on receptors were compared using two chimerical constructions based on rabbit B(2) receptors: conjugate of the B(2) receptor with green fluorescent protein (B(2)R-GFP) and the N-terminally tagged conjugate of the myc epitope with the B(2) receptor. Imaging and immunoblotting showed that B-9972 induced a persistent endocytosis of cell surface B(2) receptors in human embryonic kidney 293 cells with slow receptor degradation (weak after 3 h of treatment, important at 12 h) and B(2)R-GFP desensitization ([(3)H]bradykinin endocytosis and extracellular signal-regulated kinase 1/2 phosphorylation assays). Bradykinin was not active in this respect but when combined with captopril, induced some degradation. B-9430 reduced the endocytosis and degradation of B(2) receptors by the agonists. The results illustrate the agonist-antagonist transition in B(2) receptor peptide ligands with a constrained C-terminal structure, the importance of species in their pharmacological profile, and the possibility of selectively degrading

  10. Opioid antagonists and the sexual satiation phenomenon.

    PubMed

    Rodríguez-Manzo, G; Fernández-Guasti, A

    1995-11-01

    This study evaluates the effects of the IP injection of naloxone (0.3, 3 and 30 mg/kg) and naltrexone (0.2, 2 and 20 mg/kg) on the sexual satiation phenomenon. It was found that both antagonists exert a dose-based biphasic effect on the proportion of sexually exhausted rats displaying copulation. The intermediate doses of both opioid antagonists were more effective than the low and high doses in increasing the percentage of animals engaged in copulation. The analysis of the specific sexual behaviour parameters revealed that naloxone produces a slight inhibitory effect at the lowest dose, evidenced as an increase in the intromission number. The higher doses of this compound facilitated copulation reflected as a shortening of the ejaculation latency and the interintromission interval (III) and an increase in the copulatory rate. Naltrexone treatment had only facilitatory effects at the lower doses by reducing the III. The higher doses of naloxone (3 and 30 mg/kg) and the intermediate dose of naltrexone (2 mg/kg) decreased the spontaneous ambulatory behaviour of sexually satiated rats without impairing sexual behaviour execution. Data suggest a participation of the endogenous opioid systems in the sexual inhibition resulting from sexual exhaustion.

  11. D-Cycloserine: Agonist turned antagonist.

    PubMed

    Lanthorn, T H

    1994-10-01

    D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.

  12. Sexually antagonistic selection in human male homosexuality.

    PubMed

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-06-18

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  13. Hypocretin antagonists in insomnia treatment and beyond.

    PubMed

    Ruoff, Chad; Cao, Michelle; Guilleminault, Christian

    2011-01-01

    Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

  14. Sexually Antagonistic Selection in Human Male Homosexuality

    PubMed Central

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling ‘Darwinian paradox’. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  15. Synthesis of actively adjustable springs by antagonistic redundant actuation

    NASA Technical Reports Server (NTRS)

    Yi, Byung-Ju; Freeman, Robert A.

    1992-01-01

    A methodology for active spring generation is presented based on antagonistic redundant actuation. Antagonistic properties are characterized using an effective system stiffness. 'Antagonistic stiffness' is generated by preloading a closed-chain (parallel) linkage system. Internal load distribution is investigated along with the necessary conditions for spring synthesis. The performance and stability of a proposed active spring are shown by simulation, and applications are discussed.

  16. Evaluation of adenine as scaffold for the development of novel P2X3 receptor antagonists.

    PubMed

    Lambertucci, Catia; Sundukova, Mayya; Kachare, Dhuldeo D; Panmand, Deepak S; Dal Ben, Diego; Buccioni, Michela; Marucci, Gabriella; Marchenkova, Anna; Thomas, Ajiroghene; Nistri, Andrea; Cristalli, Gloria; Volpini, Rosaria

    2013-07-01

    Ligands that selectively block P2X3 receptors localized on nociceptive sensory fibres may be useful for the treatment of chronic pain conditions including neuropathic pain, migraine, and inflammatory pain. With the aim at exploring the suitability of adenine moiety as a scaffold for the development of antagonists of this receptor, a series of 9-benzyl-2-aminoadenine derivatives were designed and synthesized. These new compounds were functionally evaluated at rat or human P2X3 receptors expressed in human embryonic kidney (HEK) cells and on native P2X3 receptors from mouse trigeminal ganglion sensory neurons using patch clamp recording under voltage clamp configuration. The new molecules behaved as P2X3 antagonists, as they rapidly and reversibly inhibited (IC50 in the low micromolar range) the membrane currents induced via P2X3 receptor activation by the full agonist α,β-methyleneATP. Introduction of a small lipophilic methyl substituent at the 6-amino group enhanced the activity, in comparison to the corresponding unsubstituted derivative, resulting in the 9-(5-iodo-2-isopropyl-4-methoxybenzyl)-N(6)-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC50 = 1.74 ± 0.21 μM.

  17. Metabolism-guided design of short-acting calcium-sensing receptor antagonists.

    PubMed

    Southers, James A; Bauman, Jonathan N; Price, David A; Humphries, Paul S; Balan, Gayatri; Sagal, John F; Maurer, Tristan S; Zhang, Yan; Oliver, Robert; Herr, Michael; Healy, David R; Li, Mei; Kapinos, Brendon; Fate, Gwendolyn D; Riccardi, Keith A; Paralkar, Vishwas M; Brown, Thomas A; Kalgutkar, Amit S

    2010-08-12

    As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.

  18. Ligand-based molecular design of 4-benzylpiperidinealkylureas and amides as CCR3 antagonists.

    PubMed

    Jain, Vaibhav; Pandey, Ashish; Gupta, Shikhar; Mohan, C Gopi

    2010-04-01

    Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemokine receptor-3 (CCR3) play a primary role in the recruitment of eosinophils in allergic asthma. Development of novel and potent CCR3 antagonists could provide a novel mechanism for inhibition of this recruitment process, thereby preventing asthma. With the intention of designing new ligands with enhanced inhibitor potencies against CCR3, a 3D-QSAR CoMFA study was carried out on 41 4-benzylpiperidinealkylureas and amide derivatives. The best statistics of the developed CoMFA model were r (2) = 0.960, r(2)cv, n = 32 for the training set and r(2)pred, n = 9 for the test set. The generated 3D-QSAR contribution maps shed some light on the effects of the substitution pattern related to CCR3 antagonist activity.

  19. Does reproductive isolation evolve faster in larger populations via sexually antagonistic coevolution?

    PubMed

    Gay, L; Eady, P E; Vasudev, R; Hosken, D J; Tregenza, T

    2009-10-23

    Sexual conflict over reproductive investment can lead to sexually antagonistic coevolution and reproductive isolation. It has been suggested that, unlike most models of allopatric speciation, the evolution of reproductive isolation through sexually antagonistic coevolution will occur faster in large populations as these harbour greater levels of standing genetic variation, receive larger numbers of mutations and experience more intense sexual selection. We tested this in bruchid beetle populations (Callosobruchus maculatus) by manipulating population size and standing genetic variability in replicated lines derived from founders that had been released from sexual conflict for 90 generations. We found that after 19 generations of reintroduced sexual conflict, none of our treatments had evolved significant overall reproductive isolation among replicate lines. However, as predicted, measures of reproductive isolation tended to be greater among larger populations. We discuss our methodology, arguing that reproductive isolation is best examined by performing a matrix of allopatric and sympatric crosses whereas measurement of divergence requires crosses with a tester line.

  20. The effects of sigma ligands on protein release from lacrimal acinar cells: a potential agonist/antagonist assay.

    PubMed

    Schoenwald, R D; Barfknecht, C F; Shirolkar, S; Xia, E

    1995-03-03

    Sigma receptor antagonists have been proposed as leading clinical candidates for use in various psychotic disorders. Prior to clinical testing, it is imperative that a new agent be correctly identified as an antagonist and not an agonist since the latter may worsen the psychosis. For sigma-ligands many behavioral and pharmacological assays have been developed in an attempt to classify agonist/antagonist activity. These assays evaluate a response or a behavior in an animal model that can be related to clinical efficacy. However, is the action by the presumed antagonist a consequence of sigma-receptor activity? Previously we have identified sigma-receptors in acinar cells of the main lacrimal gland of the New Zealand white rabbit and have measured protein release after the addition of various N,N-disubstituted phenylalkylamine derivatives known to be sigma-ligands by receptor binding studies. Although protein release from acinar cells has been attributed to either muscarinic or alpha-adrenergic stimulation, protein release from sigma-receptor stimulation was also confirmed. In the reported studies here, we isolated and incubated acinar cells with varying concentrations of known sigma-ligands and measured protein concentration. A knowledge of the receptor profile for the disubstituted phenylalkylamines permitted experiments to be designed in which various alpha, muscarinic, serotonergic, and dopaminergic antagonists could be added in equimolar concentrations. Under the conditions of these experiments, statistically significant increases in protein release for sigma-ligands could be attributed to stimulation of sigma-receptors. Haloperidol, an apparent sigma-antagonist, caused a statistically significant decrease in protein release and also inhibited protein release when tested with a known sigma-ligand, AF2975 [N,N-dimethyl-2-phenylethylamine]. In this system, stimulation and inhibition of protein release were defined as agonist and antagonist behavior, respectively

  1. Antagonists of IAP proteins as cancer therapeutics.

    PubMed

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  2. Mutually-antagonistic interactions in baseball networks

    NASA Astrophysics Data System (ADS)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  3. Drug effects: agonistic and antagonistic processes.

    PubMed

    Flaten, Magne Arve

    2009-12-01

    The research presented here has shown that tolerance to drugs can be accelerated by conditioning processes. Placebo effects may be considered the opposite of tolerance, and we have shown that placebo effects may be objectively recorded by physiological measures (electromyography, skin conductance responses, and event-related potentials), as well as by behavioral and subjective methods. The placebo response, or more precisely, the expectation of drug effects, can add to the effect of the drug. Drug antagonistic expectations can also reverse the effect of the drug. There is some evidence that placebo effects are strongest when expectations are reinforced by administration of an active drug. Expectations have graded effects and may affect symptoms to a smaller or larger degree. Although drug effects can be considered stimuli, the investigation of the role of classical conditioning in drug use and drug effects involves special issues that must be carefully considered.

  4. Characterisation of the specific binding of the histamine H3 receptor antagonist radioligand [3H]GR168320.

    PubMed

    Brown, J D; O'Shaughnessy, C T; Kilpatrick, G J; Scopes, D I; Beswick, P; Clitherow, J W; Barnes, J C

    1996-09-12

    We have examined the specific binding of the tritiated derivative of the potent histamine H3 receptor antagonist, [3,4-3H2]-cyclohex-yl-¿[4-(3H-imidazol-4-yl)-piperidin-l-yl] iminomethyl¿- amine ([3H]GR168320), to homogenates of rat cerebral cortex. Specific binding of [3H]GR168320 at 37 degrees C associated and dissociated rapidly. Binding was saturable (Bmax 412 +/- 89 fmol/mg protein) and of high affinity (Kd 0.12 +/- 0.11 nM). Saturation studies suggested the involvement of a single site. Histamine H3 receptor agonists and antagonists inhibited [3H]GR168320 binding with high affinity. Agonist and antagonist affinities correlated when compared with affinities obtained using the tritiated histamine H3 agonist radioligand N alpha-methylhistamine.

  5. Design, synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7).

    PubMed

    Urbano, Mariangela; Guerrero, Miguel; Zhao, Jian; Velaparthi, Subash; Saldanha, S Adrian; Chase, Peter; Wang, Zhiwei; Civelli, Olivier; Hodder, Peter; Schaeffer, Marie-Therese; Brown, Steven; Rosen, Hugh; Roberts, Edward

    2012-12-01

    Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure-activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders.

  6. Identification of a sulfonamide series of CCR2 antagonists.

    PubMed

    Peace, Simon; Philp, Joanne; Brooks, Carl; Piercy, Val; Moores, Kitty; Smethurst, Chris; Watson, Steve; Gaines, Simon; Zippoli, Mara; Mookherjee, Claudette; Ife, Robert

    2010-07-01

    A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.

  7. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  8. [Effects of PAF antagonists in experimental models. Therapeutical perspectives].

    PubMed

    Desquand, S

    1993-01-01

    The discovery, during the last ten years, of Platelet Activating Factor (PAF) antagonists with different frameworks, but efficient on platelets tests, led the authors to study their activity in vivo against PAF-induced effects. These antagonists inhibit, with various potencies, the effects of PAF administration such as hypotension and bronchoconstriction in different animal species. Since PAF is assumed to play a central role in many diseases, effects of its antagonists have been studied in experimentally induced pathologies and in few clinical studies. We have been particularly interested in their effects on the first manifestation of asthma which is hypersensitivity. This manifestation is experimentally reproduced by anaphylactic bronchoconstriction, usually in the guinea-pig. Our results showed that different sensitization procedures may determine the relative efficiency of a PAF antagonist on subsequent antigen challenge. Indeed, the booster injection of antigen to a pre-sensitized animal could account for the refractoriness of anaphylactic bronchoconstriction to PAF antagonists. This booster injection mimics the clinical situation of atopic patients repeatedly exposed to allergen. Thus, it seems that immediate hypersensitivity could not be treated by the unique administration of a PAF antagonist. However, those antagonists may have more benefit in the clinical management of the late phase of asthma and of hyperreactivity and could thus provide anti-asthmatic drugs. PAF antagonists may have also therapeutical effects in septic shock, in myocardial ischemia and cardiac rhythm disturbances, in brain damage following cerebral ischemia and neurological trauma, in gastric and intestinal damages or in some inflammatory reactions.

  9. Microbial antagonists of Verticillium dahliae colonize cotton root system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Verticillium wilt remains one of the most severe diseases affecting cotton production in Uzbekistan. We are investigating microbial antagonist to control this pathogen. To this end, we have identified several antagonists of Verticillium dahliae (Bacillus sp. 234, Bacillus sp. 3, Streptomyces roseofl...

  10. Third Generation Mineralocorticoid Receptor Antagonists; Why We Need a Fourth

    PubMed Central

    Gomez-Sanchez, Elise

    2015-01-01

    The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated. PMID:26466326

  11. Pharmacological and clinical importance of narcotic antagonists and mixed antagonists — use in cardiology

    PubMed Central

    Coltart, D. John; Malcolm, Alasdair D.

    1979-01-01

    1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of morphine, diamorphine, pavaveretum, pethidine and pentazocine are reviewed. 3 Clinical experience with the new antagonist analgesic buprenorphine is reported. 4 These studies indicate that buprenorphine may be the agent of choice for the relief of severe pain in patients with unstable circulation. PMID:465292

  12. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

  13. Identification of Thyroid Receptor Ant/Agonists in Water Sources Using Mass Balance Analysis and Monte Carlo Simulation

    PubMed Central

    Shi, Wei; Wei, Si; Hu, Xin-xin; Hu, Guan-jiu; Chen, Cu-lan; Wang, Xin-ru; Giesy, John P.; Yu, Hong-xia

    2013-01-01

    Some synthetic chemicals, which have been shown to disrupt thyroid hormone (TH) function, have been detected in surface waters and people have the potential to be exposed through water-drinking. Here, the presence of thyroid-active chemicals and their toxic potential in drinking water sources in Yangtze River Delta were investigated by use of instrumental analysis combined with cell-based reporter gene assay. A novel approach was developed to use Monte Carlo simulation, for evaluation of the potential risks of measured concentrations of TH agonists and antagonists and to determine the major contributors to observed thyroid receptor (TR) antagonist potency. None of the extracts exhibited TR agonist potency, while 12 of 14 water samples exhibited TR antagonistic potency. The most probable observed antagonist equivalents ranged from 1.4 to 5.6 µg di-n-butyl phthalate (DNBP)/L, which posed potential risk in water sources. Based on Monte Carlo simulation related mass balance analysis, DNBP accounted for 64.4% for the entire observed antagonist toxic unit in water sources, while diisobutyl phthalate (DIBP), di-n-octyl phthalate (DNOP) and di-2-ethylhexyl phthalate (DEHP) also contributed. The most probable observed equivalent and most probable relative potency (REP) derived from Monte Carlo simulation is useful for potency comparison and responsible chemicals screening. PMID:24204563

  14. Antagonistic autoregulation speeds up a homogeneous response in Escherichia coli

    PubMed Central

    Rodrigo, Guillermo; Bajic, Djordje; Elola, Ignacio; Poyatos, Juan F.

    2016-01-01

    By integrating positive and negative feedback loops, biological systems establish intricate gene expression patterns linked to multistability, pulsing, and oscillations. This depends on the specific characteristics of each interlinked feedback, and thus one would expect additional expression programs to be found. Here, we investigate one such program associated with an antagonistic positive and negative transcriptional autoregulatory motif derived from the multiple antibiotic resistance (mar) system of Escherichia coli. We studied the dynamics of the system by combining a predictive mathematical model with high-resolution experimental measures of the response both at the population and single-cell level. We show that in this motif the weak positive autoregulation does not slow down but rather enhances response speedup in combination with a strong negative feedback loop. This balance of feedback strengths anticipates a homogeneous population phenotype, which we corroborate experimentally. Theoretical analysis also emphasized the specific molecular properties that determine the dynamics of the mar phenotype. More broadly, response acceleration could provide a rationale for the presence of weak positive feedbacks in other biological scenarios exhibiting these interlinked regulatory architectures. PMID:27796341

  15. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    PubMed Central

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  16. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  17. Discovery tactics to mitigate toxicity risks due to reactive metabolite formation with 2-(2-hydroxyaryl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3h)-one derivatives, potent calcium-sensing receptor antagonists and clinical candidate(s) for the treatment of osteoporosis.

    PubMed

    Kalgutkar, Amit S; Griffith, David A; Ryder, Tim; Sun, Hao; Miao, Zhuang; Bauman, Jonathan N; Didiuk, Mary T; Frederick, Kosea S; Zhao, Sabrina X; Prakash, Chandra; Soglia, John R; Bagley, Scott W; Bechle, Bruce M; Kelley, Ryan M; Dirico, Kenneth; Zawistoski, Michael; Li, Jianke; Oliver, Robert; Guzman-Perez, Angel; Liu, Kevin K C; Walker, Daniel P; Benbow, John W; Morris, Joel

    2010-06-21

    The synthesis and structure-activity relationship studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones as antagonists of the human calcium receptor (CaSR) have been recently disclosed [ Didiuk et al. ( 2009 ) Bioorg. Med. Chem. Lett. 19 , 4555 - 4559 ). On the basis of its pharmacology and disposition attributes, (R)-2-(2-hydroxyphenyl)-3-(1-phenylpropan-2-yl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (1) was considered for rapid advancement to first-in-human (FIH) trials to mitigate uncertainty surrounding the pharmacokinetic/pharmacodynamic (PK/PD) predictions for a short-acting bone anabolic agent. During the course of metabolic profiling, however, glutathione (GSH) conjugates of 1 were detected in human liver microsomes in an NADPH-dependent fashion. Characterization of the GSH conjugate structures allowed insight(s) into the bioactivation pathway, which involved CYP3A4-mediated phenol ring oxidation to the catechol, followed by further oxidation to the electrophilic ortho-quinone species. While the reactive metabolite (RM) liability raised concerns around the likelihood of a potential toxicological outcome, a more immediate program goal was establishing confidence in human PK predictions in the FIH study. Furthermore, the availability of a clinical biomarker (serum parathyroid hormone) meant that PD could be assessed side by side with PK, an ideal scenario for a relatively unprecedented pharmacologic target. Consequently, progressing 1 into the clinic was given a high priority, provided the compound demonstrated an adequate safety profile to support FIH studies. Despite forming identical RMs in rat liver microsomes, no clinical or histopathological signs prototypical of target organ toxicity were observed with 1 in in vivo safety assessments in rats. Compound 1 was also devoid of metabolism-based mutagenicity in in vitro (e.g., Salmonella Ames) and in vivo assessments (micronuclei induction in bone marrow) in rats. Likewise, metabolism

  18. [3-(1H-imidazol-4-yl)propyl]guanidines containing furoxan moieties: a new class of H3-antagonists endowed with NO-donor properties.

    PubMed

    Bertinaria, Massimo; Stilo, Antonella Di; Tosco, Paolo; Sorba, Giovanni; Poli, Enzo; Pozzoli, Cristina; Coruzzi, Gabriella; Fruttero, Roberta; Gasco, Alberto

    2003-04-03

    Synthesis and pharmacological characterisation of a series of products obtained by coupling the H(3)-antagonist SKF 91486 through appropriate spacers with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan substructures, devoid of NO-donating properties, are reported. All the products were tested for their H(3)-antagonistic and H(2)-agonistic properties on electrically-stimulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. The whole series of compounds displayed good H(3)-antagonist behaviour and feeble partial H(2)-agonist activity. Among furoxan derivatives, the benzenesulfonyl hybrid 28, a good NO-donor, triggered a dual NO-dependent muscle relaxation and H(3)-antagonistic effect on guinea-pig intestine.

  19. Dotarizine versus flunarizine as calcium antagonists in chromaffin cells.

    PubMed Central

    Villarroya, M; Gandía, L; Lara, B; Albillos, A; López, M G; García, A G

    1995-01-01

    1. Dotarizine is a novel piperazine derivative structurally related to flunarizine that is currently being evaluated in clinical trials for its antimigraine and antivertigo effects. This clinical profile may be related to its Ca2+ antagonist properties. Therefore, the actions of both compounds as calcium antagonists were compared in bovine chromaffin cells. 2. Dotarizine and flunarizine blocked 45Ca2+ uptake into K+ depolarized chromaffin cells (70 mM K+/0.5 mM Ca2+ for 60 s) in a concentration-dependent manner, with IC50s of 4.8 and 6.7 microM, respectively. 3. Dotarizine and flunarizine also inhibited the whole-cell Ca2+ and Ba2+ currents (ICa, IBa) in voltage-clamped chromaffin cells, induced by depolarizing test pulses to 0 mV, during 50 ms, from a holding potential of -80 mV. Blockade exhibited IC50s of 4 microM for dotarizine and 2.2 microM for flunarizine. Dotarizine increased the rate of inactivation of ICa and IBa; inhibition of whole-cell currents was use-dependent. 4. Transient increases of the cytosolic Ca2+ concentration, [Ca2+]i, produced by K+ stimulation (70 mM K+ for 5 s) of single fura-2-loaded chromaffin cells, were also inhibited by dotarizine and flunarizine with IC50s of 1.2 and 0.6 microM, respectively. Upon washout of dotarizine, the [Ca2+]i increases recovered fully after 5-10 min. In contrast, the responses remained largely inhibited 10 min after washing out flunarizine. 5. Catecholamine release induced by K+ stimulation (10-s pulses of 70 mM) was inhibited by dotarizine with an IC50 of 2.6 microM and by flunarizine with an IC50 of 1.2 microM. The blocking effects of both compounds developed slowly, and was fully established after 20-30 min of superfusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7881736

  20. Molecular determinants of the species selectivity of neurokinin type 1 receptor antagonists.

    PubMed

    Pradier, L; Habert-Ortoli, E; Emile, L; Le Guern, J; Loquet, I; Bock, M D; Clot, J; Mercken, L; Fardin, V; Garret, C

    1995-02-01

    Most nonpeptide neurokinin (NK)1 antagonists display a marked difference in affinity for rat versus human NK1 receptors. The molecular basis for the species selectivity of RP67580 and CP96,345 has been previously addressed [J. Biol. Chem. 267:25668-25671 (1992); J. Biol. Chem. 268:2319-2323 (1993)]. We are extending these previous results to additional NK1 antagonists, which are members of different chemical families. Included is a new perhydroisoindolol, RPR100893, which unlike its parent compound (RP67580) is human receptor selective. Chimeric rat/human NK1 receptors, as well as rat and human mutant NK1 receptors, were constructed and expressed in COS-1 cells, and affinities for substance P and the various antagonists were determined in binding studies. With human receptor-selective antagonists, the rat R290(S-->I) mutation was the most effective in increasing antagonist affinity (from 7- to 23-fold). Combination with the R116(L-->V) mutation led to an additional increase in affinity for trans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N- methyl-N-(phenylmethyl)-L-tyrosineamide (a derivative of FK888) and to nearly full human receptor affinity for RPR100893 and (+/-)-CP99,994. Based on the gains in affinities, these results confirm and extend the role of residues 116 and 290 of the NK1 receptor in the species selectivity of these three new human receptor-selective NK1 antagonists. In comparison, the affinity of RP67580, the least selective molecule, was most affected by changes at position 116, and combination with mutations at either position 97 (V-->E) or position 290 led to the human receptor phenotype. For the heterosteroid KAN610857, modifications of the rat receptor at positions 97 and 290, and to a lesser degree position 116, were the most effective in reducing affinity. Two double-mutants [R(97,290) and R(116,290)], although different from those identified for RP67580, also displayed human receptor-like affinity. Therefore, the molecular determinants of

  1. Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists.

    PubMed

    Zhang, Meng-Qi; Zhang, Xiao-Le; Li, Yan; Fan, Wen-Jia; Wang, Yong-Hua; Hao, Ming; Zhang, Shu-Wei; Ai, Chun-Zhi

    2011-01-01

    MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R(2) (ncv) of 0.868, R(2) (pred) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R(2) (ncv) = 0.899, R(2) (pred) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R(2) (ncv) = 0.715, R(2) (pred) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R(7), R(3) and position A benefit activity I of the antagonists, but decrease it when projected in R(8) and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity

  2. Endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Dupuis, J; Hoeper, M M

    2008-02-01

    The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.

  3. Antagonists for acute oral cadmium chloride intoxication

    SciTech Connect

    Basinger, M.A.; Jones, M.M.; Holscher, M.A.; Vaughn, W.K.

    1988-01-01

    An examination has been carried out on the relative efficacy of a number of chelating agents when acting as antagonists for oral cadmium chloride intoxication in mice. The compounds were administered orally after the oral administration of cadmium chloride at 1 mmol/kg. Of the compounds examined, several were useful in terms of enhancing survival, but by far the most effective in both enhancing survival and leaving minimal residual levels of cadmium in the liver and the kidney, was meso-2,3-dimercaptosuccinic acid (DMSA). Several polyaminocarboxylic acids also enhanced survival. The most effective of these in reducing liver and kidney levels of cadmium were diethylenetriaminepentaacetic acid (DTPA), trans-1,2-diaminocyclohexane-N,N,N'N'-tetraacetic acid (CDTA), and triethylenetetraminehexaacetic acid (TTHA). D-Penicillamine (DPA) was found to promote survival but also led to kidney cadmium levels higher than those found in the controls. Sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) was as effective in promoting survival as DMSA but left levels of cadmium in the kidney and liver that were approximately four times greater than those found with DMSA.

  4. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells

    NASA Astrophysics Data System (ADS)

    Bertoletti, Antonio; Sette, Alessandro; Chisari, Francis V.; Penna, Amalia; Levrero, Massimo; Carli, Marco De; Fiaccadori, Franco; Ferrari, Carlo

    1994-06-01

    IT has been suggested that mutations within immunodominant cytotoxic T-lymphocyte (CTL) epitopes may be exploited by viruses to evade protective immune responses critical for clearance1-4. Viral escape could originate from passive mechanisms, such as mutations within crucial CTL epitopes, either affecting major histocompatibility complex binding or T-cell antigen receptor (TCR) recognition. Additionally, it has recently been shown that substitutions of TCR contact sites can yield analogue peptides that can still interact with the T-cell receptor but be unable to deliver a full stimulatory signal, thus inducing anergy5 or acting as an antagonist for the TCR6-8. We report here that hepatitis B virus isolates derived from two chronically infected patients display variant epitopes that act as natural TCR antagonists with the capacity to inhibit the CTL response to the wild-type epitope. During natural infection, TCR antagonist mutations of CTL epitopes could contribute to the development of viral persistence, especially if the antiviral CTL response is monospecific or the epitope is strongly immunodominant.

  5. Generation of a highly diverse panel of antagonistic chicken monoclonal antibodies against the GIP receptor

    PubMed Central

    Könitzer, Jennifer D.; Pan, Qi; Augustin, Robert; Bandholtz, Sebastian; Harriman, William; Izquierdo, Shelley

    2017-01-01

    ABSTRACT Raising functional antibodies against G protein-coupled receptors (GPCRs) is challenging due to their low density expression, instability in the absence of the cell membrane's lipid bilayer and frequently short extracellular domains that can serve as antigens. In addition, a particular therapeutic concept may require an antibody to not just bind the receptor, but also act as a functional receptor agonist or antagonist. Antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor may open up new therapeutic modalities in the treatment of diabetes and obesity. As such, a panel of monoclonal antagonistic antibodies would be a useful tool for in vitro and in vivo proof of concept studies. The receptor is highly conserved between rodents and humans, which has contributed to previous mouse and rat immunization campaigns generating very few usable antibodies. Switching the immunization host to chicken, which is phylogenetically distant from mammals, enabled the generation of a large and diverse panel of monoclonal antibodies containing 172 unique sequences. Three-quarters of all chicken-derived antibodies were functional antagonists, exhibited high-affinities to the receptor extracellular domain and sampled a broad epitope repertoire. For difficult targets, including GPCRs such as GIPR, chickens are emerging as valuable immunization hosts for therapeutic antibody discovery. PMID:28055305

  6. Identification of a pepducin acting as S1P3 receptor antagonist.

    PubMed

    Severino, Beatrice; Incisivo, Giuseppina Maria; Fiorino, Ferdinando; Bertolino, Antonio; Frecentese, Francesco; Barbato, Francesco; Manganelli, Serena; Maggioni, Giada; Capasso, Domenica; Caliendo, Giuseppe; Santagada, Vincenzo; Sorrentino, Raffaella; Roviezzo, Fiorentina; Perissutti, Elisa

    2013-11-01

    Sphingosine-1-phosphate (S1P) is a bioactive lipid with key functions in the immune, inflammatory, and cardiovascular systems. S1P exerts its action through the interaction with a family of five known G protein-coupled receptors, named S1P(1-5). Among them, S1P(3) has been implicated in the pathological processes of a number of diseases, including sepsis and cancer. KRX-725 (compound 1) is a pepducin that mimics the effects of S1P by triggering specifically S1P(3). Here, aiming to identify novel S1P(3) antagonists, we carried out an alanine scanning analysis to address the contribution of the side chains of each amino acid residue to the peptide function. Then, deleted peptides from both the C- and N-terminus were prepared in order to determine the minimal sequence for activity and to identify the structural requirements for agonistic and, possibly, antagonistic behaviors. The pharmacological results of the Ala-scan derived compounds (2-10) suggested a high tolerance of the pepducin 1 to amino acid substitutions. Importantly, the deleted peptide 16 has the ability to inhibit, in a dose-dependent manner, both pepducin 1-induced vasorelaxation and fibroblast proliferation. Finally, a computational analysis was performed on the prepared compounds, showing that the supposed antagonists 16 and 17 appeared to be aligned with each other but not with the others. These results suggested a correlation between specific conformations and activities.

  7. Generation of a highly diverse panel of antagonistic chicken monoclonal antibodies against the GIP receptor.

    PubMed

    Könitzer, Jennifer D; Pramanick, Shreya; Pan, Qi; Augustin, Robert; Bandholtz, Sebastian; Harriman, William; Izquierdo, Shelley

    2017-01-05

    Raising functional antibodies against G protein-coupled receptors (GPCRs) is challenging due to their low density expression, instability in the absence of the cell membrane's lipid bilayer and frequently short extracellular domains that can serve as antigens. In addition, a particular therapeutic concept may require an antibody to not just bind the receptor, but also act as a functional receptor agonist or antagonist. Antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor may open up new therapeutic modalities in the treatment of diabetes and obesity. As such, a panel of monoclonal antagonistic antibodies would be a useful tool for in vitro and in vivo proof of concept studies. The receptor is highly conserved between rodents and humans, which has contributed to previous mouse and rat immunization campaigns generating very few usable antibodies. Switching the immunization host to chicken, which is phylogenetically distant from mammals, enabled the generation of a large and diverse panel of monoclonal antibodies containing 172 unique sequences. Three-quarters of all chicken-derived antibodies were functional antagonists, exhibited high-affinities to the receptor extracellular domain and sampled a broad epitope repertoire. For difficult targets, including GPCRs such as GIPR, chickens are emerging as valuable immunization hosts for therapeutic antibody discovery.

  8. Antagonistic Effect of Pseudomonas sp. CMI-1 on
Foodborne Pathogenic Listeria monocytogenes.

    PubMed

    Belák, Ágnes; Maráz, Anna

    2015-06-01

    Bacterial isolates derived from food or raw food materials of animal origin were screened for potential antagonistic activity against foodborne pathogenic Listeria monocytogenes. Using the agar spot method, ten out of the 94 tested bacteria showed antilisterial activity. All of the antagonistic isolates identified by sequence analysis as strains of the genus Pseudomonas were able to inhibit the growth of all the examined Listeria species including the ruminal pathogenic L. ivanovii and the opportunistic human pathogenic L. innocua. Pseudomonas sp. CMI-1 had the highest inhibitory effect on the growth of different Listeria strains. Co-culturing studies revealed that the inhibition of L. monocytogenes could not be achieved efficiently. Although the population of the Pseudomonas sp. CMI-1 strain increased by up to 10 orders of magnitude during 2 days of culturing period at 20 °C in the presence of L. monocytogenes, the cell count of the pathogen also increased by approx. 6 orders of magnitude. At the same time, appropriate inhibition of cell-free supernatants generated from 6-day-old cultures of Pseudomonas sp. CMI-1 was observed. The inhibitory compound of this antagonistic strain is presumably a chromopeptide siderophore, whose activity and production can be affected by iron supplementation, and which had an absorption maximum typical of siderophores of fluorescent Pseudomonas species. Production of the antilisterial substance was influenced by the oxygen concentration, as in static cultures the concentration of the siderophore was higher than in shake flask cultures.

  9. Antagonistic Effect of Pseudomonas sp. CMI-1 on
Foodborne Pathogenic Listeria monocytogenes

    PubMed Central

    Maráz, Anna

    2015-01-01

    Summary Bacterial isolates derived from food or raw food materials of animal origin were screened for potential antagonistic activity against foodborne pathogenic Listeria monocytogenes. Using the agar spot method, ten out of the 94 tested bacteria showed antilisterial activity. All of the antagonistic isolates identified by sequence analysis as strains of the genus Pseudomonas were able to inhibit the growth of all the examined Listeria species including the ruminal pathogenic L. ivanovii and the opportunistic human pathogenic L. innocua. Pseudomonas sp. CMI-1 had the highest inhibitory effect on the growth of different Listeria strains. Co-culturing studies revealed that the inhibition of L. monocytogenes could not be achieved efficiently. Although the population of the Pseudomonas sp. CMI-1 strain increased by up to 10 orders of magnitude during 2 days of culturing period at 20 °C in the presence of L. monocytogenes, the cell count of the pathogen also increased by approx. 6 orders of magnitude. At the same time, appropriate inhibition of cell-free supernatants generated from 6-day-old cultures of Pseudomonas sp. CMI-1 was observed. The inhibitory compound of this antagonistic strain is presumably a chromopeptide siderophore, whose activity and production can be affected by iron supplementation, and which had an absorption maximum typical of siderophores of fluorescent Pseudomonas species. Production of the antilisterial substance was influenced by the oxygen concentration, as in static cultures the concentration of the siderophore was higher than in shake flask cultures. PMID:27904352

  10. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    PubMed Central

    Khanfar, Mohammad A.; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  11. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    PubMed

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  12. The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

    PubMed

    Lochner, Martin; Thompson, Andrew J

    2016-09-01

    Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

  13. Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect

    PubMed Central

    Claussen, Catherine M; Witte, Lindsey J; Dafny, Nachum

    2015-01-01

    Methylphenidate (MPD) is a readily prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD) and moreover is used illicitly by youths for its cognitive-enhancing effects and recreation. MPD exposure in rodents elicits increased locomotor activity. Repetitive MPD exposure leads to further augmentation of their locomotor activity. This behavioral response is referred to as behavioral sensitization. Behavioral sensitization is used as an experimental marker for a drug’s ability to elicit dependence. There is evidence that dopamine (DA) is a key player in the acute and chronic MPD effect; however, the role of DA in the effects elicited by MPD is still debated. The objective of this study was to investigate the role of D1 and/or D2 DA receptors in the acute and chronic effect of MPD on locomotor activity. The study lasted for 12 consecutive days. Seven groups of male Sprague Dawley® rats were used. A single D1 or D2 antagonist was given before and after acute and chronic MPD administration. Single injection of D1 DA antagonist was able to significantly attenuate the locomotor activity when given prior to the initial MPD exposure and after repetitive MPD exposure, while the D2 DA antagonist partially attenuated the locomotor activity only when given before the second MPD exposure. The results show the role, at least in part, of the D1 DA receptor in the mechanism of behavioral sensitization, whereas the D2 DA receptor only partially modulates the response to acute and chronic MPD. PMID:27186140

  14. Bipiperidinyl carboxylic acid amides as potent, selective, and functionally active CCR4 antagonists.

    PubMed

    Kuhn, Cyrille F; Bazin, Marc; Philippe, Laurence; Zhang, Jiansu; Tylaska, Laurie; Miret, Juan; Bauer, Paul H

    2007-09-01

    A cell-based assay for the chemokine G-protein-coupled receptor CCR4 was developed, and used to screen a small-molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer.

  15. Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects.

    PubMed

    Yuan, Chun-Su; Israel, Robert J

    2006-05-01

    Methylnaltrexone is an investigational peripheral opioid receptor antagonist, a quaternary derivative of naltrexone. Methylnaltrexone has greater polarity and lower lipid solubility, thus it does not cross the blood-brain barrier in humans. Methylnaltrexone offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating the opioid withdrawal symptoms that are predominantly mediated by receptors in the CNS. This article reviews preclinical studies and clinical opioid bowel dysfunction trial data, and briefly discusses other potential roles of this compound in clinical practice.

  16. Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.

    PubMed

    Mathews, Jennifer L; Peng, Xuemei; Xiong, Wennan; Zhang, Ao; Negus, S Stevens; Neumeyer, John L; Bidlack, Jean M

    2005-11-01

    Previous research has shown that compounds with mixed kappa and mu activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a kappa opioid receptor agonist and a mu opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K(i) values of 0.078 and 0.20 nM for the kappa and mu opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[(35) S]thiotriphosphate) binding assay, MCL-145 produced an E(max) value of 80% for the kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.

  17. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    SciTech Connect

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  18. Anthropomorphic finger antagonistically actuated by SMA plates.

    PubMed

    Engeberg, Erik D; Dilibal, Savas; Vatani, Morteza; Choi, Jae-Won; Lavery, John

    2015-08-20

    Most robotic applications that contain shape memory alloy (SMA) actuators use the SMA in a linear or spring shape. In contrast, a novel robotic finger was designed in this paper using SMA plates that were thermomechanically trained to take the shape of a flexed human finger when Joule heated. This flexor actuator was placed in parallel with an extensor actuator that was designed to straighten when Joule heated. Thus, alternately heating and cooling the flexor and extensor actuators caused the finger to flex and extend. Three different NiTi based SMA plates were evaluated for their ability to apply forces to a rigid and compliant object. The best of these three SMAs was able to apply a maximum fingertip force of 9.01N on average. A 3D CAD model of a human finger was used to create a solid model for the mold of the finger covering skin. Using a 3D printer, inner and outer molds were fabricated to house the actuators and a position sensor, which were assembled using a multi-stage casting process. Next, a nonlinear antagonistic controller was developed using an outer position control loop with two inner MOSFET current control loops. Sine and square wave tracking experiments demonstrated minimal errors within the operational bounds of the finger. The ability of the finger to recover from unexpected disturbances was also shown along with the frequency response up to 7 rad s(-1). The closed loop bandwidth of the system was 6.4 rad s(-1) when operated intermittently and 1.8 rad s(-1) when operated continuously.

  19. [Angiotensin II receptor antagonists: different or equivalent?].

    PubMed

    Mounier-Vehier, C; Devos, P

    ARA-II: Angiotensin II receptor antagonists (ARA-II) belong to a recent class of antihypertensive drugs whose mechanism of action is similar to converting enzyme inhibitors (CEI). ARA-II are particularly interesting due to the excellent clinical and biological tolerance, similar to placebo, and their antihypertensive efficacy, comparable with classical drug classes. PUBLISHED TRIALS: A meta-analysis, published by Conlin in the American Journal of Hypertension, suggests that ARA-II, specifically losartan, valsartan, irbesartan and candesartan, have an equipotent blood pressure lowering effect. The careful lecture of this meta-analysis however discloses a faulty methodology from which no valid conclusion can be drawn. Since this early publication, several other comparative studies have been published. These multicentric, randomized double-blind studies enrolled a sufficient number of patients and demonstrated a clinical difference between certain ARA-II at usual dosages. CLINICAL PRACTICE: These studies do have an impact on everyday practice. For the practitioner, the goal is to obtain and then maintain a long-term and optimal reduction in the blood pressure level (reduction or prevention of target-organ disorders and cardiovascular complications of high blood pressure). This reduction in the cardiovascular risk will also depend directly on tolerance and compliance to the antihypertensive treatment. This element must also be considered in assessing treatment efficacy, independent of the blood pressure lowering effect. The results of several other studies will be published in 2001-2003. These large-scale studies on ARA-II related morbidity and mortality will be most useful in determining the role of these drugs in different therapeutic strategies compared with other drug classes.

  20. The pharmacological properties of lipophilic calcium antagonists.

    PubMed

    van Zwieten, P A

    1998-01-01

    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  1. RS-1748, a novel CC chemokine receptor 4 antagonist, inhibits ovalbumin-induced airway inflammation in guinea pigs.

    PubMed

    Nakagami, Yasuhiro; Kawase, Yumi; Yonekubo, Kazuki; Nosaka, Emi; Etori, Maki; Takahashi, Sakiko; Takagi, Nana; Fukuda, Takeshi; Kuribayashi, Takeshi; Nara, Futoshi; Yamashita, Makoto

    2010-01-01

    CC chemokine receptor 4 (CCR4) is generally recognized as a preferential marker for T helper 2 cells, and we have previously reported morpholine-derivative CCR4 antagonists, RS-1154 and RS-1269. Here, we investigate the pharmacological profiles of a novel pyrimidine-derivative CCR4 antagonist, 2-{4-[2-(diethylamino)ethoxy]phenyl}-N-(2,4-difluorobenzyl)-5-fluoropyrimidin-4-amine (RS-1748), which showed potency to inhibit the bindings of [(125)I]CCL17 and [(35)S]GTPgammaS to human CCR4-expressing Chinese hamster ovary (CHO) cells with IC(50) values of 59.9 nM and 18.4 nM, respectively. Furthermore, RS-1748 inhibited ovalbumin-induced airway inflammation in guinea pigs at a dose of 10 mg/kg. These results indicate that RS-1748 would be a promising lead compound for developing a therapeutic agent against asthma.

  2. Complications of TNF-α antagonists and iron homeostasis

    EPA Science Inventory

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  3. Solution structures and molecular interactions of selective melanocortin receptor antagonists.

    PubMed

    Lee, Chul-Jin; Yun, Ji-Hye; Lim, Sung-Kil; Lee, Weontae

    2010-12-01

    The solution structures and inter-molecular interaction of the cyclic melanocortin antagonists SHU9119, JKC363, HS014, and HS024 with receptor molecules have been determined by NMR spectroscopy and molecular modeling. While SHU9119 is known as a nonselective antagonist, JKC363, HS014, and HS024 are selective for the melanocortin subtype-4 receptor (MC4R) involved in modulation of food intake. Data from NMR and molecular dynamics suggest that the conformation of the Trp9 sidechain in the three MC4R-selective antagonists is quite different from that of SHU9119. This result strongly supports the concept that the spatial orientation of the hydrophobic aromatic residue is more important for determining selectivity than the presence of a basic, "arginine-like" moiety responsible for biological activity. We propose that the conformation of hydrophobic residues of MCR antagonists is critical for receptor-specific selectivity.

  4. Structure-based drug design identifies novel LPA3 antagonists

    PubMed Central

    Fells, James I.; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L.

    2009-01-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA3 antagonist (IC50=4504 nM) in a virtual screening effort to optimize a dual LPA2&3 antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA3 receptor by 200 nM LPA with IC50 values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA3 receptor antagonists. The results of the combined computational and experimental screening are reported. PMID:19800804

  5. Structure-based drug design identifies novel LPA3 antagonists.

    PubMed

    Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L

    2009-11-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.

  6. Assortative mating by fitness and sexually antagonistic genetic variation.

    PubMed

    Arnqvist, Göran

    2011-07-01

    Recent documentations of sexually antagonistic genetic variation in fitness have spurred an interest in the mechanisms that may act to maintain such variation in natural populations. Using individual-based simulations, I show that positive assortative mating by fitness increases the amount of sexually antagonistic genetic variance in fitness, primarily by elevating the equilibrium frequency of heterozygotes, over most of the range of sex-specific selection and dominance. Further, although the effects of assortative mating by fitness on the protection conditions of polymorphism in sexually antagonistic loci were relatively minor, it widens the protection conditions under most reasonable scenarios (e.g., under heterozygote superiority when fitness is averaged across the sexes) but can also somewhat narrow the protection conditions under other circumstances. The near-ubiquity of assortative mating in nature suggests that it may contribute to upholding standing sexually antagonistic genetic variation in fitness.

  7. Vasopressin-receptor antagonist therapy in patients with hyponatraemia.

    PubMed

    Vachharajani, Tushar; Vachharajani, Vidula

    2007-07-01

    Hyponatraemia often complicates the treatment of underlying conditions in patients who are seriously ill. Arginine vasopressin receptor antagonists block the action of arginine vasopressin and correct sodium and water imbalance in patients with euvolaemic or hypervolaemic hyponatraemia.

  8. Antagonistic interactions of soil pseudomonads are structured in time.

    PubMed

    Kraemer, Susanne A; Soucy, Jean-Paul R; Kassen, Rees

    2017-04-06

    Social interactions have been invoked as potential major selective forces structuring natural microbial communities and thus may help explain the astonishing bacterial diversity of natural ecosystems. Here, we investigate the prevalence and structure of exotoxin-mediated antagonistic interactions among free-living soil Pseudomonas strains collected over the course of two years at distances of up to one kilometer. Unlike some previous studies on antagonistic interactions among natural isolates, we found the prevalence of exotoxin-mediated inhibitions to be relatively low. When present, antagonistic interactions show a weakly negative relationship with genetic relatedness and metabolic similarity. Intriguingly, isolates sampled from the same growing season were significantly more likely to inhibit each other than they were to inhibit isolates from different growing seasons. Exotoxin-mediated antagonistic interactions between soil pseudomonads thus seem to be structured in time but do not appear to be a major selective force structuring free-living soil bacterial communities of soil pseudomonads.

  9. Structure-activity relationships of benzothiazole GPR35 antagonists.

    PubMed

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  10. Structure-activity relationships of benzothiazole GPR35 antagonists

    PubMed Central

    Abdalhameed, Manahil M.; Zhao, Pingwei; Hurst, Dow P.; Reggio, Patricia H.; Abood, Mary E.; Croatt, Mitchell P.

    2017-01-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound. PMID:27989666

  11. Discovery of Novel Triazole-Based Opioid Receptor Antagonists

    PubMed Central

    Zhang, Qiang; Keenan, Susan M.; Peng, Youyi; Nair, Anil C.; Yu, Seong Jae; Howells, Richard D.; Welsh, William J.

    2009-01-01

    We report the computer-aided design, chemical synthesis, and biological evaluation of a novel family of δ opioid receptor (DOR) antagonists containing a 1,2,4-triazole core structure that are structurally distinct from other known opioid receptor active ligands. Among those δ antagonists sharing this core structure, 8 exhibited strong binding affinity (Ki = 50 nM) for the DOR and appreciable selectivity for δ over μ and opioid receptors (δ/μ = 80; δ/κ > 200). PMID:16821764

  12. Pediatric heart failure therapy with beta-adrenoceptor antagonists.

    PubMed

    Foerster, Susan R; Canter, Charles E

    2008-01-01

    Management of chronic heart failure in pediatrics has been altered by the adult literature showing improvements in mortality and hospitalization rates with the use of beta-adrenoceptor antagonists (beta-blockers) for routine therapy of all classes of ischemic and non-ischemic heart failure. Many pediatric heart failure specialists have incorporated these agents into their routine management of pediatric heart failure related to dilated cardiomyopathy or ventricular dysfunction in association with congenital heart disease. Retrospective and small prospective case series have shown encouraging improvements in cardiac function and symptoms, but interpretation has been complicated by the high rate of spontaneous recovery in pediatric patients. A recently completed pediatric double-blind, randomized, placebo-controlled clinical trial showed no difference between placebo and two doses of carvedilol over a 6-month period of follow-up, with significant improvement of all three groups over the course of evaluation. Experience with adults has suggested that only certain beta-blockers, including carvedilol, bisoprolol, nebivolol, and metoprolol succinate, should be used in the treatment of heart failure and that patients with high-grade heart failure may derive the most benefit. Other studies surmise that early or prophylactic use of these medications may alter the risk of disease progression in some high-risk subsets, such as patients receiving anthracyclines or those with muscular dystrophy. This article reviews these topics using experience as well as data from all the recent pediatric studies on the use of beta-blockers to treat congestive heart failure, especially when related to systolic ventricular dysfunction.

  13. Discovery and optimization of potent and selective functional antagonists of the human adenosine A2B receptor.

    PubMed

    Bedford, Simon T; Benwell, Karen R; Brooks, Teresa; Chen, Ijen; Comer, Mike; Dugdale, Sarah; Haymes, Tim; Jordan, Allan M; Kennett, Guy A; Knight, Anthony R; Klenke, Burkhard; LeStrat, Loic; Merrett, Angela; Misra, Anil; Lightowler, Sean; Padfield, Anthony; Poullennec, Karine; Reece, Mark; Simmonite, Heather; Wong, Melanie; Yule, Ian A

    2009-10-15

    We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.

  14. CXCR2 receptor antagonists: a medicinal chemistry perspective.

    PubMed

    Dwyer, Michael P; Yu, Younong

    2014-01-01

    Dysregulated leukocyte recruitment is believed to be a key contributor to various acute and chronic inflammatory disorders which can lead to serious pathological consequences. Chemokines are small molecular weight proteins that have been shown to be imperative in the direction of leukocytes to the sites of inflammation. In humans, several of these chemokines (CXCL8 and CXCL1) are elevated in inflammatory disorders such as asthma, arthritis, and chronic obstructive pulmonary disease (COPD). These chemokines modulate their downstream effects thru G-protein coupled receptors, such as CXCR2, making the identification of small-molecule antagonists of this receptor attractive towards developing novel therapies to treat inflammatory conditions. Since the first report of a CXCR2 receptor antagonist in 1998, there has been a considerable effort conducted mainly in the pharmaceutical industry to identify novel classes of CXCR2 receptor antagonists. Over a dozen distinct classes of CXCR2 receptor antagonists have been reported in the literature to date with a number of these compounds having reached mid-stage clinical trials. This review will provide a broad overview the medicinal chemistry efforts over the past 15 years towards the identification of CXCR2 receptor antagonists. The discussion will focus upon the early preclinical space covering the structure activity relationships (SAR), pharmacology, as well in preclinical in vivo evaluation for the different series of CXCR2 receptor antagonists. In addition, the available clinical data for the most advanced compounds in the clinic will be discussed and along with a perspective of the area moving forward.

  15. Neuronal death enhanced by N-methyl-d-aspartate antagonists

    PubMed Central

    Ikonomidou, Chrysanthy; Stefovska, Vanya; Turski, Lechoslaw

    2000-01-01

    Glutamate promotes neuronal survival during brain development and destroys neurons after injuries in the mature brain. Glutamate antagonists are in human clinical trials aiming to demonstrate limitation of neuronal injury after head trauma, which consists of both rapid and slowly progressing neurodegeneration. Furthermore, glutamate antagonists are considered for neuroprotection in chronic neurodegenerative disorders with slowly progressing cell death only. Therefore, humans suffering from Huntington's disease, characterized by slowly progressing neurodegeneration of the basal ganglia, are subjected to trials with glutamate antagonists. Here we demonstrate that progressive neurodegeneration in the basal ganglia induced by the mitochondrial toxin 3-nitropropionate or in the hippocampus by traumatic brain injury is enhanced by N-methyl-d-aspartate antagonists but ameliorated by α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonists. These observations reveal that N-methyl-d-aspartate antagonists may increase neurodestruction in mature brain undergoing slowly progressing neurodegeneration, whereas blockade of the action of glutamate at α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors may be neuroprotective. PMID:11058158

  16. Molecular docking and 3D-QSAR studies on the glucocorticoid receptor antagonistic activity of hydroxylated polychlorinated biphenyls.

    PubMed

    Liu, S; Luo, Y; Fu, J; Zhou, J; Kyzas, G Z

    2016-01-01

    The glucocorticoid receptor (GR) antagonistic activities of hydroxylated polychlorinated biphenyls (HO-PCBs) were recently characterised. To further explore the interactions between HO-PCBs and the GR, and to elucidate structural characteristics that influence the GR antagonistic activity of HO-PCBs, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Comparative molecular similarity indices analysis (CoMSIA) was performed using both ligand- and receptor-based alignment schemes. Results generated from the receptor-based model were found to be more satisfactory, with q(2) of 0.632 and r(2) of 0.931 compared with those from the ligand-based model. Some internal validation strategies (e.g. cross-validation analysis, bootstrapping analysis and Y-randomisation) and an external validation method were used respectively to further assess the stability and predictive ability of the derived model. Graphical interpretation of the model provided some insights into the structural features that affected the GR antagonistic activity of HO-PCBs. Molecular docking studies revealed that some key residues were critical for ligand-receptor interactions by forming hydrogen bonds (Glu540) and hydrophobic interactions with ligands (Ile539, Val543 and Trp577). Although CoMSIA sometimes depends on the alignment of the molecules, the information provided is beneficial for predicting the GR antagonistic activities of HO-PCB homologues and is helpful for understanding the binding mechanisms of HO-PCBs to GR.

  17. New adenosine A2A receptor antagonists: actions on Parkinson's disease models.

    PubMed

    Pinna, Annalisa; Volpini, Rosaria; Cristalli, Gloria; Morelli, Micaela

    2005-04-11

    The 8-substituted 9-ethyladenine derivatives: 8-bromo-9-ethyladenine (ANR 82), 8-ethoxy- 9-ethyladenine (ANR 94), and 8-furyl-9-ethyladenine (ANR 152) have been characterized in vitro as adenosine receptor antagonists. Adenosine is deeply involved in the control of motor behaviour and substantial evidences indicate that adenosine A(2A) receptor antagonists improve motor deficits in animal models of Parkinson's disease. On this basis, the efficacy of ANR 82, ANR 94, and ANR 152 in rat models of Parkinson's disease was evaluated. All compounds tested reversed the catalepsy induced by haloperidol. However, in unilaterally 6-hydroxydopamine-lesioned rats, only ANR 94 and ANR 152 potentiated l-dihydroxy-phenylalanine (l-DOPA) effect on turning behaviour and induced contralateral turning behaviour in rats sensitised to l-DOPA. Taken together the results of this study indicate that some 8-substituted 9-ethyladenine derivatives ameliorate motor deficits in rat models of Parkinson's disease, suggesting a potential therapeutic role of these compounds.

  18. Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells.

    PubMed

    Bianchini, Francesca; Peppicelli, Silvia; Fabbrizzi, Pierangelo; Biagioni, Alessio; Mazzanti, Benedetta; Menchi, Gloria; Calorini, Lido; Pupi, Alberto; Trabocchi, Andrea

    2017-01-01

    Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.

  19. Determination of a PAF antagonist pharmacophore using combined Molecular Electrostatic Potential and Molecular Lipophilicity Potential.

    PubMed

    Le Solleu, H; Langlois, M H; Kummer, E; Dubost, J P

    1994-11-01

    PAF is a potent lipid mediator involved in many pathological disorders, such as platelet aggregation, immuno-inflammatory reactions, vascular disorders, septic shock and bronchoconstriction. We chose to study the electronic and lipophilic properties of eleven PAF antagonists, comprising five tetrahydrofuran derivatives, four hetrazepines, the ginkgolide BN-52021 and the pyrrolo-thiazole derivative RP-59227. A Molecular Electrostatic Potential (MEP) contour drawn at -25 kCal/Mol shows three electronegative areas in most compounds. Two areas can be considered as analogous to those described in the so-called "Cache-Oreille" (Earmuff) Model. Molecular Lipophilicity Potential (MLP) analysis allows us to characterise one hydrophilic area, localised at the same place as one of the electronegative areas, and two lipophilic areas, of which the biggest draws a typical "sock" contour. These three areas represent the minimal requirements for a high affinity to the PAF receptor. MEP and MLP results are here combined to propose a pharmacophore for PAF antagonists, including two lipophilic areas, two hydrophilic and electronegative areas and an electronegative zone with no particular hydrophilic behaviour.

  20. Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro.

    PubMed

    Zhang, Qiao; Wang, Shifeng; Yu, Yangyang; Sun, Shengnan; Zhang, Yuxin; Zhang, Yanling; Yang, Wei; Li, Shiyou; Qiao, Yanjiang

    2016-08-02

    Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 µM in the HEK293/ETAR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR.

  1. Hemoglobin derivatives

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003371.htm Hemoglobin derivatives To use the sharing features on this page, please enable JavaScript. Hemoglobin derivatives are altered forms of hemoglobin . Hemoglobin is ...

  2. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

    PubMed Central

    Broussolle, Emmanuel; Laurencin, Chloé; Bernard, Emilien; Thobois, Stéphane; Danaila, Teodor; Krack, Paul

    2015-01-01

    Background Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. Results In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin. Discussion Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia. PMID:26417535

  3. GnRH antagonists may affect endometrial receptivity

    PubMed Central

    Rackow, Beth W.; Kliman, Harvey J.; Taylor, Hugh S.

    2009-01-01

    Study objective HOXA10 is an essential regulator of endometrial receptivity. To determine the effect of gonadotropin releasing hormone (GnRH) antagonists on endometrial receptivity we assessed endometrial HOXA10 expression in GnRH antagonist, GnRH agonist, and natural cycles. Design Prospective case-control study Setting University academic medical center Patients Nineteen subjects were included: 12 subjects underwent controlled ovarian hyperstimulation (COH) with recombinant follicle stimulating hormone (rFSH) and used either a GnRH antagonist or a GnRH agonist; 7 control subjects underwent natural cycles. Interventions Pipelle endometrial biopsies were obtained 11 days after human chorionic gonadotropin (hCG) administration or spontaneous luteinizing hormone (LH) surge in untreated cycles, respectively. Immunohistochemistry was used to assess HOXA10 protein expression in endometrial glands and stroma. Main outcome measure(s) Endometrial HOXA10 protein expression Results HOXA10 expression was significantly decreased in endometrial stromal cells in GnRH antagonist treated cycles compared with GnRH agonist treated cycles or natural cycle controls. There was no significant difference in glandular cell HOXA10 expression among the three groups. Conclusions Use of GnRH antagonists may be associated with impaired HOXA10 expression in endometrial stromal cells, and thus may affect endometrial receptivity. PMID:18410932

  4. Pharmacophore development for antagonists at α1 adrenergic receptor subtypes

    NASA Astrophysics Data System (ADS)

    Bremner, J. B.; Coban, B.; Griffith, R.

    1996-12-01

    Many receptors, including α1 adrenergic receptors, have a range of subtypes. This offers possibilities for the development of highly selective antagonists with potentially fewer detrimental effects. Antagonists developed for α1A receptors, for example, would have potential in the treatment of benign prostatic hyperplasia. As part of the molecular design process, structural features necessary for the selective affinity for α1A and α1B adrenergic receptors have been investigated. The molecular modelling software (particularly the Apex module) of Molecular Simulations, Inc. was used to develop pharmacophore models for these two subtypes. Low-energy conformations of a set of known antagonists were used as input, together with a classification of the receptor affinity data. The biophores proposed by the program were evaluated and pharmacophores were proposed. The pharmacophore models were validated by testing the fit of known antagonists, not included in the training set. The critical structural feature for selectivity between the α1A and α1B adrenergic receptor sites is the distance between the basic nitrogen atom and the centre of an aromatic ring system. This will be exploited in the design and synthesis of structurally new selective antagonists for these sites.

  5. A highly toxic morphine-3-glucuronide derivative.

    PubMed

    Salvatella, Mariona; Arsequell, Gemma; Valencia, Gregorio; Rodríguez, Raquel E

    2004-02-23

    By the coupling of octylamine to the uronic acid function of morphine-3-glucuronide (M3G) a new glycoconjugate (morphine-3-octylglucuronamide, M3GOAM) was prepared. When assayed in both rats and mice up to ng/kg (i.p.) doses none of the animals survived. The aliphatic octyl chain may be the lethal factor since a closely related derivative (M3GNH2), was not toxic and showed similar opioid antagonist properties than naloxone.

  6. Mixed antagonistic effects of bilobalide at rho1 GABAC receptor.

    PubMed

    Huang, S H; Duke, R K; Chebib, M; Sasaki, K; Wada, K; Johnston, G A R

    2006-01-01

    Bilobalide was found to be a moderately potent antagonist with a weak use-dependent effect at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methodology. Antagonism of bilobalide at homomeric rho(1) GABA(C) receptors appeared to be mixed. At low concentration, bilobalide (3 microM) caused a parallel right shift and surmountable GABA maximal response of the GABA dose-response curve characteristic of a competitive antagonist. At high concentrations, bilobalide (10-100 microM) caused nonparallel right shifts and reduced maximal GABA responses of GABA dose-response curves characteristic of a noncompetitive antagonist. The potency of bilobalide appears to be dependent on the concentrations of GABA and was more potent at lower GABA concentrations. The mechanism of action of bilobalide at rho(1) GABA(C) receptors appears to be similar to that of the chloride channel blocker picrotoxinin.

  7. Enhancer Responses to Similarly Distributed Antagonistic Gradients in Development

    PubMed Central

    Zinzen, Robert P; Papatsenko, Dmitri

    2007-01-01

    Formation of spatial gene expression patterns in development depends on transcriptional responses mediated by gene control regions, enhancers. Here, we explore possible responses of enhancers to overlapping gradients of antagonistic transcriptional regulators in the Drosophila embryo. Using quantitative models based on enhancer structure, we demonstrate how a pair of antagonistic transcription factor gradients with similar or even identical spatial distributions can lead to the formation of distinct gene expression domains along the embryo axes. The described mechanisms are sufficient to explain the formation of the anterior and the posterior knirps expression, the posterior hunchback expression domain, and the lateral stripes of rhomboid expression and of other ventral neurogenic ectodermal genes. The considered principles of interaction between antagonistic gradients at the enhancer level can also be applied to diverse developmental processes, such as domain specification in imaginal discs, or even eyespot pattern formation in the butterfly wing. PMID:17500585

  8. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    NASA Astrophysics Data System (ADS)

    Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

    1993-06-01

    Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

  9. Discovery of the improved antagonistic prolactin variants by library screening.

    PubMed

    Liu, Yun; Gong, Wei; Breinholt, Jens; Nørskov-Lauritsen, Leif; Zhang, Jinchao; Ma, Qinhong; Chen, Jianhe; Panina, Svetlana; Guo, Wei; Li, Tengkun; Zhang, Jingyuan; Kong, Meng; Liu, Zibing; Mao, Jingjing; Christensen, Leif; Hu, Sean; Wang, Lingyun

    2011-11-01

    Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.

  10. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

    SciTech Connect

    Zuercher, William J.; Buckholz†, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M.

    2010-08-12

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  11. Scaffold variations in amine warhead of histamine H₃ receptor antagonists.

    PubMed

    Wingen, Kerstin; Stark, Holger

    2013-12-01

    The histamine H₃ receptor (H₃R) is involved in numerous regulatory neurotransmission processes and there-fore, is a prominent target for centrally occurring disease with some promising clinical candidates. Previous research resulted in the identification of a core pharmacophore blueprint for H₃R antagonists/inverse agonists, which when inserted in a molecule, mostly ensures acceptable affinity. Nevertheless, variations of scaffold and peripheral areas can increase potency and pharmacokinetic profile of drug candidates. The variations in amine scaffolds of antagonists for this aminergic GPCR are of special importance.

  12. Barnidipine, a long-acting slow onset calcium antagonist.

    PubMed

    Korstanje, C

    2000-11-01

    Barnidipine is a stereochemically pure dihydropyridine calcium antagonist with a high potency. The drug showed a slow onset and long-lasting vasorelaxating effect in vitro, and strong antihypertensive activity in hypertension models. Barnidipine was shown to have a high vasoselectivity and offered protection in cardiac and renal ischaemia models. The in vitro drug:drug interaction profile suggests a low potential for clinically relevant interactions with concomitant medication. It can be anticipated that barnidipine is an attractive calcium antagonist, offering good blood pressure control without compensatory baroreflex activity.

  13. Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models

    PubMed Central

    Fischer, Wolfgang; Franke, Heike; Krügel, Ute; Müller, Heiko; Dinkel, Klaus; Lord, Brian; Letavic, Michael A.; Henshall, David C.; Engel, Tobias

    2016-01-01

    The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders. PMID:27281030

  14. 20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.

    PubMed

    Fousteris, Manolis A; Schubert, Undine; Roell, Daniela; Roediger, Julia; Bailis, Nikolaos; Nikolaropoulos, Sotiris S; Baniahmad, Aria; Giannis, Athanassios

    2010-10-01

    Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.

  15. Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: Novel small molecule antagonists of PGE2 receptor EP2

    PubMed Central

    Ganesh, Thota

    2016-01-01

    Recent studies underscore that prostaglandin-E2 (PGE2) exerts mostly proinflammatory effects in chronic CNS and peripheral disease models, mainly through a specific prostanoid receptor EP2. However, very few highly characterized EP2 receptor antagonists have been reported until recently, when Pfizer and Emory University published two distinct classes of EP2 antagonists with good potency, selectivity and pharmacokinetics. The purpose of this article is to evaluate recently published patents WO 2012177618 A1 and US-2014/0179750 A1 from Emory, which describe a number of cinnamic amide- and amide-derivatives as a potent antagonists of EP2 receptor, and their neuroprotective effects in in vitro and in an in vivo model. A selected compound from this patent(s) also attenuates prostate cancer cell growth and invasion in vitro, suggesting these compounds should be developed for therapeutic use. PMID:25772215

  16. Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: novel small molecule antagonists of prostaglandin-E2 receptor EP2.

    PubMed

    Ganesh, Thota

    2015-07-01

    Recent studies underscore that prostaglandin-E2 exerts mostly proinflammatory effects in chronic CNS and peripheral disease models, mainly through a specific prostanoid receptor EP2. However, very few highly characterized EP2 receptor antagonists have been reported until recently, when Pfizer and Emory University published two distinct classes of EP2 antagonists with good potency, selectivity and pharmacokinetics. The purpose of this article is to evaluate recently published patents WO 2012/177618 A1 and US-2014/0179750 A1 from Emory, which describe a number of cinnamic amide- and amide-derivatives as a potent antagonists of EP2 receptor, and their neuroprotective effects in in vitro and in an in vivo model. A selected compound from this patent(s) also attenuates prostate cancer cell growth and invasion in vitro, suggesting these compounds should be developed for therapeutic use.

  17. Is there a place for combining angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists in the treatment of hypertension, renal disease or congestive heart failure?

    PubMed

    Taylor, A A

    2001-09-01

    Angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 antagonists have proven to be effective and well tolerated antihypertensive agents. They also exhibit unique cardioprotective and renoprotective properties in patients with comorbid conditions such as congestive heart failure and proteinuria or renal insufficiency. This benefit is observed most dramatically in diabetic persons. Although inconclusive, the results of a limited number of clinical trials support the notion that additive antihypertensive, cardioprotective, and renoprotective effects may be obtained with combined used of angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 antagonists in some patients. More studies are needed to confirm the findings of these preliminary studies, and to define more clearly those subsets of patients who might derive the greatest benefit from angiotensin-converting enzyme inhibitor-angiotensin II receptor subtype 1 antagonist combination therapy.

  18. The ebolavirus VP24 interferon antagonist

    PubMed Central

    Zhang, Adrianna P.P.; Abelson, Dafna M.; Bornholdt, Zachary A.; Liu, Tong; Woods, Jr, Virgil L.; Saphire, Erica Ollmann

    2012-01-01

    Suppression during the early phases of the immune system often correlates directly with a fatal outcome for the host. The ebolaviruses, some of the most lethal viruses known, appear to cripple initial stages of the host defense network via multiple distinct paths. Two of the eight viral proteins are critical for immunosuppression. One of these proteins is VP35, which binds double-stranded RNA and antagonizes several antiviral signaling pathways.1,2 The other protein is VP24, which binds transporter molecules to prevent STAT1 translocation.3 A more recent discovery is that VP24 also binds STAT1 directly,4 suggesting that VP24 may operate in at least two separate branches of the interferon pathway. New crystal structures of VP24 derived from pathogenic and nonpathogenic ebolaviruses reveal its novel, pyramidal fold, upon which can be mapped sites required for virulence and for STAT1 binding. These structures of VP24, and new information about its direct binding to STAT1, provide avenues by which we may explore its many roles in the viral life cycle, and reasons for differences in pathogenesis among the ebolaviruses. PMID:23076242

  19. Retention and Outcome in a Narcotic Antagonist Treatment Program.

    ERIC Educational Resources Information Center

    Capone, Thomas; And Others

    1986-01-01

    Patients in an outpatient narcotic antagonist treatment program were followed through their course of treatment. Those who remained longer were found to enter treatment with more stable employment records and less recent opiate use. They also appeared more successful at termination, with better vocational stability, less extraneous drug use, and…

  20. Endothelin receptor antagonists and cardiovascular diseases of aging.

    PubMed

    Love, M P; McMurray, J J

    2001-01-01

    Our understanding of the role of the endothelin system in human cardiovascular physiology and pathophysiology has evolved very rapidly since the initial description of its constituent parts in 1988. Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system and has potent vasoconstrictor, mitogenic and antinatriuretic properties which have implicated it in the pathophysiology of a number of cardiovascular diseases. The effects of ET-1 have been shown to be mediated by 2 principal endothelin receptor subtypes: ET(A) and ET(B). The development of a range of peptidic and nonpeptidic endothelin receptor antagonists represents an exciting breakthrough in human cardiovascular therapeutics. Two main classes of endothelin receptor antagonist have been developed for possible human therapeutic use: ET(A)-selective and nonselective antagonists. Extensive laboratory and clinical research with these agents has highlighted their promise in various cardiovascular diseases. Randomised, placebo-controlled clinical trials have yielded very encouraging results in patients with hypertension and chronic heart failure with more preliminary data suggesting a possible role in the treatment and prevention of atherosclerosis and stroke. Much more research is needed, however, before endothelin receptor antagonists can be considered for clinical use.

  1. Fine-Tuning Development Through Antagonistic Peptides: An Emerging Theme.

    PubMed

    Lee, Jin Suk; De Smet, Ive

    2016-12-01

    Peptide ligand-receptor kinase interactions have emerged as a key component of plant growth and development. Now, highly related small signaling peptides have been shown to act antagonistically on the same receptor kinase, providing new insights into how plants optimize developmental processes using competitive peptides.

  2. Novel benzopolycyclic amines with NMDA receptor antagonist activity.

    PubMed

    Valverde, Elena; Sureda, Francesc X; Vázquez, Santiago

    2014-05-01

    A new series of benzopolycyclic amines active as NMDA receptor antagonists were synthesized. Most of them exhibited increased activity compared with related analogues previously published. All the tested compounds were more potent than clinically approved amantadine and one of them displayed a lower IC50 value than memantine, an anti-Alzheimer's approved drug.

  3. Non-NMDA receptor antagonist-induced drinking in rat

    NASA Technical Reports Server (NTRS)

    Xu, Z.; Johnson, A. K.

    1998-01-01

    Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

  4. [Medical economics evaluation of 5-HT3 receptor antagonist drugs].

    PubMed

    Utsunomiya, Junpei; Hirano, Shigeki; Fukui, Aiko; Funabashi, Kazuaki; Deguchi, Yuko; Yamada, Susumu; Naito, Kazuyuki

    2010-10-01

    At Komaki City Hospital, the drug cost in connection with cancer chemotherapy was re-examined as part of improved management along with the introduction of DPC in July 2008. With due attention to the 5-HT3 receptor antagonists, both the change from injections to oral drugs and the change from brand-name drugs to generic drugs were tried between July 2008 and June 2009. After that, in order to examine the economic impact of these changes, we investigated and analyzed the number of medications, the cost of medicine purchased, and the average drug cost per medication of the 5-HT3 receptor antagonists between April 2008 and September 2009. As a result, the cost of 5-HT3 receptor antagonists purchased decreased greatly, and the impact of the improvement was mainly due to the change to oral drugs, and partially to the change to generic drugs. Therefore, from the viewpoint of hospital economic improvement in DPC, it was thought that the change to oral drugs(5-HT3 receptor antagonists)is given top priority.

  5. Medium-Induced Antagonistic Behavior in Staphylococcus Aureus.

    ERIC Educational Resources Information Center

    Benathen, Isaiah A.

    1992-01-01

    Antagonism is the production of substances by microorganisms that inhibit or prevent the growth of other bacteria. This paper demonstrates the antagonistic behavior of gram-positive coccus on the B. subtilis and Enterococcus faecalis gram-positive microorganisms, showing that the process of antagonism is sometimes dependent on the nutritional…

  6. The Effect of Antagonist Muscle Sensory Input on Force Regulation

    PubMed Central

    Onushko, Tanya; Schmit, Brian D.; Hyngstrom, Allison

    2015-01-01

    The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years), healthy subjects performed constant isometric knee flexion contractions (agonist) at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback) during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%), subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40%) between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical) are likely involved. PMID:26186590

  7. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    SciTech Connect

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  8. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    PubMed

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

  9. Pseudomonas glareae sp. nov., a marine sediment-derived bacterium with antagonistic activity.

    PubMed

    Romanenko, Lyudmila A; Tanaka, Naoto; Svetashev, Vassilii I; Mikhailov, Valery V

    2015-06-01

    An aerobic, Gram-negative, motile, rod-shaped bacterium designated KMM 9500(T) was isolated from a sediment sample collected from the Sea of Japan seashore. Comparative 16S rRNA gene sequence analysis affiliated strain KMM 9500(T) to the genus Pseudomonas as a distinct subline clustered with Pseudomonas marincola KMM 3042(T) and Pseudomonas segetis KCTC 12331(T) sharing the highest similarities of 98 and 97.9 %, respectively. Strain KMM 9500(T) was characterized by mainly possessing ubiquinone Q-9, and by the predominance of C18:1 ω7c, C16:1 ω7c, and C16:0 followed by C12:0 in its fatty acid profile. Polar lipids consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unknown aminophospholipid, and unknown phospholipids. Strain KMM 9500(T) was found to inhibit growth of Gram-negative and Gram-positive indicatory microorganisms. Based on the phylogenetic analysis and distinctive phenotypic characteristics, strain 9500(T) is concluded to represent a novel species of the genus Pseudomonas, for which the name Pseudomonas glareae sp. nov. is proposed. The type strain of the species is strain KMM 9500(T) (=NRIC 0939(T)).

  10. Characteristics of a Bacteriocin Derived from Streptococcus faecalis var. zymogenes Antagonistic to Diplococcus peumoniae

    PubMed Central

    Bottone, Edward; Allerhand, Jona; Pisano, Michael A.

    1971-01-01

    A bacteriocin-producing strain of Streptococcus faecalis var. zymogenes (E-1) was isolated from clinical material (conjunctiva). The active substance differed from bacteriocins described by other investigators primarily in its spectrum of antibacterial activity, especially by its marked inhibition of Diplococcus pneumoniae. The E-1 bacteriocin also inhibited nonhemolytic strains of enterococci as well as one-third of the Viridans group of streptococcal strains investigated. The degree of inhibition, however, as indicated by the size of the zones against the latter organisms, was significantly reduced. No activity was detected against any of the strains belonging to the following groups of bacteria: hemolytic enterococci, beta-hemolytic streptococci, nonhemolytic streptococci, staphylococci, and various gram-negative species. Similarly, three strains each of Bacillus cereus and Listeria monocytogenes and one strain of Erysipelothrix insidiosa were not inhibited. The bacteriocin was able to diffuse through bacterial membranes as well as cellulose dialyzer tubing. It was inactivated by heating to 80 C for 20 min but resisted inactivation by either trypsin or chloroform. Images PMID:4398532

  11. Two 1,4-dihydropyridine derivatives with potential calcium-channel antagonist activity.

    PubMed

    Linden, Anthony; Safak, Cihat; Simşek, Rahime; Gündüz, Miyase G

    2011-02-01

    The title compounds, benzyl 4-(3-chloro-2-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate, C(23)H(19)ClFNO(3), (I), and 3-pyridylmethyl 4-[2-fluoro-3-(trifluoromethyl)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C(26)H(24)F(4)N(2)O(3), (II), belong to a class of 1,4-dihydropyridines whose members sometimes display calcium modulatory properties. The 1,4-dihydropyridine ring in each structure has a shallower than usual shallow-boat conformation and is nearly planar in (I). In each structure, the halogen-substituted benzene ring is oriented such that the halogen substituents are in a synperiplanar orientation with respect to the 1,4-dihydropyridine ring plane. The oxocyclopentene ring in (I) is planar, while the oxocyclohexene ring in (II) has a half-chair conformation, which is less commonly observed than the envelope conformation usually found in related compounds. In (I), the frequently observed intermolecular N-H···O hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighbouring molecule links the molecules into extended chains; there are no other significant intermolecular interactions. By contrast, the amine group in (II) forms an N-H···N hydrogen bond with the pyridine ring N atom of a neighbouring molecule. Additional C-H···O interactions complete a two-dimensional hydrogen-bonded network. The halogen-substituted benzene ring has a weak intramolecular π-π interaction with the pyridine ring. A stronger π-π interaction occurs between the 1,4-dihydropyridine rings of centrosymmetrically related molecules.

  12. Rice Bran Amendment Suppresses Potato Common Scab by Increasing Antagonistic Bacterial Community Levels in the Rhizosphere.

    PubMed

    Tomihama, Tsuyoshi; Nishi, Yatsuka; Mori, Kiyofumi; Shirao, Tsukasa; Iida, Toshiya; Uzuhashi, Shihomi; Ohkuma, Moriya; Ikeda, Seishi

    2016-07-01

    Potato common scab (PCS), caused by pathogenic Streptomyces spp., is a serious disease in potato production worldwide. Cultural practices, such as optimizing the soil pH and irrigation, are recommended but it is often difficult to establish stable disease reductions using these methods. Traditionally, local farmers in southwest Japan have amended soils with rice bran (RB) to suppress PCS. However, the scientific mechanism underlying disease suppression by RB has not been elucidated. The present study showed that RB amendment reduced PCS by repressing the pathogenic Streptomyces population in young tubers. Amplicon sequencing analyses of 16S ribosomal RNA genes from the rhizosphere microbiome revealed that RB amendment dramatically changed bacterial composition and led to an increase in the relative abundance of gram-positive bacteria such as Streptomyces spp., and this was negatively correlated with PCS disease severity. Most actinomycete isolates derived from the RB-amended soil showed antagonistic activity against pathogenic Streptomyces scabiei and S. turgidiscabies on R2A medium. Some of the Streptomyces isolates suppressed PCS when they were inoculated onto potato plants in a field experiment. These results suggest that RB amendment increases the levels of antagonistic bacteria against PCS pathogens in the potato rhizosphere.

  13. In vitro metabolism studies of new adenosine A 2A receptor antagonists.

    PubMed

    Marucci, Gabriella; Finaurini, Sara; Buccioni, Michela; Lammi, Carmen; Kandhavelu, Meenakshisundaram; Volpini, Rosaria; Ricciutelli, Massimo; Angeli, Piero; Commandeur, Jan N M; Cristalli, Gloria

    2008-12-01

    Evidence, obtained in rodent and primate models of Parkinson's disease (PD) and in preliminary clinical trials, indicates that adenosine A(2A) receptor antagonists might represent a promising non-dopaminergic therapeutic tool for the treatment of PD. Recently, we have reported the biological evaluation of 8-substituted 9-ethyladenines (ANR) as new A(2A) receptor antagonists, three of which (ANR 82, ANR 94, and ANR 152) showed high efficacy in in vivo models for Parkinson's. Understanding the metabolic pathways of new drug candidates is an important aspect of drug discovery. The ANR compounds have been investigated in order to clarify their activity on rat liver microsomes, and more specifically on recombinant human cytochrome P450 2D6 (CYP2D6). The metabolites of all three compounds were detected by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The results indicate that this class of 9-ethyladenines is metabolized only to a fraction of 1.5-5%. These compounds also act as potent mechanism-based inhibitors of CYP450 and in particular of human isoform CYP2D6. Kinetic-analysis of enzyme inactivation was used to describe the effect of these time-dependent inhibitors and to derive the inhibition parameters K(inact) and K(i) defined with respect to the O-demethylation of dextromethorphan.

  14. Antagonistic interactions peak at intermediate genetic distance in clinical and laboratory strains of Pseudomonas aeruginosa

    PubMed Central

    2012-01-01

    Background Bacteria excrete costly toxins to defend their ecological niche. The evolution of such antagonistic interactions between individuals is expected to depend on both the social environment and the strength of resource competition. Antagonism is expected to be weak among highly similar genotypes because most individuals are immune to antagonistic agents and among dissimilar genotypes because these are unlikely to be competing for the same resources and antagonism should not yield much benefit. The strength of antagonism is therefore expected to peak at intermediate genetic distance. Results We studied the ability of laboratory strains of Pseudomonas aeruginosa to prevent growth of 55 different clinical P. aeruginosa isolates derived from cystic fibrosis patients. Genetic distance was determined using genetic fingerprints. We found that the strength of antagonism was maximal among genotypes of intermediate genetic distance and we show that genetic distance and resource use are linked. Conclusions Our results suggest that the importance of social interactions like antagonism may be modulated by the strength of resource competition. PMID:22439760

  15. Protective effect of CR 1409 (cholecystokinin antagonist) on experimental pancreatitis in rats and mice.

    PubMed

    Makovec, F; Bani, M; Cereda, R; Chistè, R; Revel, L; Rovati, L C; Setnikar, I; Rovati, L A

    1986-01-01

    CR 1409, a glutaramic acid derivative with competitive cholecystokinin-antagonistic activity, was administered IP and evaluated in comparison with proglumide (the model CCK-receptor antagonist), gabexate (protease inhibitor) and PGE2 (cytoprotective) on two different models of experimental pancreatitis. Acute pancreatitis was induced in mice by six IP injections of 50 micrograms/kg caerulein at hourly intervals. The drugs were administered 30 minutes before each caerulein administration. Blood samples and pancreata were collected 3 hours after the last caerulein injection. In the second experiment, pancreatitis was induced in rats by injecting 0.3 ml 6% sodium taurocholate interstitially into the pancreas. The drugs were administered twice, 30 minutes before and 3 hours after taurocholate. The animals were killed 6 hours after laparotomy and blood samples and pancreata were collected. CR 1409 exhibited on both pancreatitis models a protective effect in a dose range of 0.3-10 mg/kg. Proglumide exhibited a protective activity at higher doses (200-400 mg/kg). Gabexate and PGE2 were effective only in pancreatitis induced by taurocholate in a dose range of 30-60 mg/kg and 60-130 micrograms/kg respectively. These results, showing a high protective effect of CR 1409 on different models of acute pancreatitis, suggest an important role of CCK in the pathogenesis of pancreatitis.

  16. Novel antagonists of serotonin-4 receptors: synthesis and biological evaluation of pyrrolothienopyrazines.

    PubMed

    Lemaître, Stéphane; Lepailleur, Alban; Bureau, Ronan; Butt-Gueulle, Sabrina; Lelong-Boulouard, Véronique; Duchatelle, Pascal; Boulouard, Michel; Dumuis, Aline; Daveu, Cyril; Lezoualc'h, Frank; Pfeiffer, Bruno; Dauphin, François; Rault, Sylvain

    2009-03-15

    Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.

  17. Effect of SDF-1/Cxcr4 Signaling Antagonist AMD3100 on Bone Mineralization in Distraction Osteogenesis.

    PubMed

    Xu, Jia; Chen, Yuanfeng; Liu, Yang; Zhang, Jinfang; Kang, Qinglin; Ho, Kiwai; Chai, Yimin; Li, Gang

    2017-03-16

    Distraction osteogenesis (DO) is a widely applied technique in orthopedics surgery, which involves rapid stem cell migration, homing, and differentiation. Interactions between the chemokine receptor Cxcr4 and its ligand, stromal derived factor-1 (SDF-1), regulate hematopoietic stem cell trafficking to the ischemic area and induce their subsequent differentiation. Here, we examined SDF-1 expression and further investigated the role of SDF-1/Cxcr4 signaling antagonist AMD3100 during bone regeneration in rat DO model. The results showed that expression levels of SDF-1 and osteogenic genes were higher in DO zones than in the fracture zones, and SDF-1 expression level was the highest at the termination of the distraction phase. Radiological, mechanical, and histological analyses demonstrated that the local administration of AMD3100 (400 μM) to DO rats significantly inhibited new bone formation. In the rat bone marrow mesenchymal stem cells culture, comparing to the group treated with osteogenic induction medium, AMD3100 supplement led to a considerable decrease in the expression of alkaline phosphatase and early osteogenic marker genes. However, the amount of calcium deposits in rat MSCs did not differ between the groups. Therefore, our study demonstrated that the DO process induced higher expression of SDF-1, which collated to rapid induction of callus formation. Local application of SDF-1/Cxcr4 signaling antagonist AMD3100 significantly inhibited bone mineralization and osteogenesis in DO, which may represent a potential therapeutic approach to the enhancement of bone consolidation in patients undergoing DO.

  18. Diversity, distribution, and antagonistic activities of rhizobacteria of Panax notoginseng

    PubMed Central

    Fan, Ze-Yan; Miao, Cui-Ping; Qiao, Xin-Guo; Zheng, You-Kun; Chen, Hua-Hong; Chen, You-Wei; Xu, Li-Hua; Zhao, Li-Xing; Guan, Hui-Lin

    2015-01-01

    Background Rhizobacteria play an important role in plant defense and could be promising sources of biocontrol agents. This study aimed to screen antagonistic bacteria and develop a biocontrol system for root rot complex of Panax notoginseng. Methods Pure-culture methods were used to isolate bacteria from the rhizosphere soil of notoginseng plants. The identification of isolates was based on the analysis of 16S ribosomal RNA (rRNA) sequences. Results A total of 279 bacteria were obtained from rhizosphere soils of healthy and root-rot notoginseng plants, and uncultivated soil. Among all the isolates, 88 showed antagonistic activity to at least one of three phytopathogenic fungi, Fusarium oxysporum, Fusarium solani, and Phoma herbarum mainly causing root rot disease of P. notoginseng. Based on the 16S rRNA sequencing, the antagonistic bacteria were characterized into four clusters, Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetesi. The genus Bacillus was the most frequently isolated, and Bacillus siamensis (Hs02), Bacillus atrophaeus (Hs09) showed strong antagonistic activity to the three pathogens. The distribution pattern differed in soil types, genera Achromobacter, Acidovorax, Brevibacterium, Brevundimonas, Flavimonas, and Streptomyces were only found in rhizosphere of healthy plants, while Delftia, Leclercia, Brevibacillus, Microbacterium, Pantoea, Rhizobium, and Stenotrophomonas only exist in soil of diseased plant, and Acinetobacter only exist in uncultivated soil. Conclusion The results suggest that diverse bacteria exist in the P. notoginseng rhizosphere soil, with differences in community in the same field, and antagonistic isolates may be good potential biological control agent for the notoginseng root-rot diseases caused by F. oxysporum, Fusarium solani, and Panax herbarum. PMID:27158229

  19. Design, synthesis, and structure-activity relationship of novel CCR2 antagonists.

    PubMed

    Kothandaraman, Shankaran; Donnely, Karla L; Butora, Gabor; Jiao, Richard; Pasternak, Alexander; Morriello, Gregori J; Goble, Stephen D; Zhou, Changyou; Mills, Sander G; Maccoss, Malcolm; Vicario, Pasquale P; Ayala, Julia M; Demartino, Julie A; Struthers, Mary; Cascieri, Margaret A; Yang, Lihu

    2009-03-15

    A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.

  20. Marching into battle: synchronized walking diminishes the conceptualized formidability of an antagonist in men

    PubMed Central

    Fessler, Daniel M. T.; Holbrook, Colin

    2014-01-01

    Paralleling behaviours in other species, synchronized movement is central to institutionalized collective human activities thought to enhance cooperation, and experiments demonstrate that synchrony has this effect. The influence of synchrony on cooperation may derive from an evolutionary history wherein such actions served to signal coalitional strength to both participants and observers—including adversaries. If so, then synchronous movement should diminish individuals' estimations of a foe's formidability. Envisioned physical size and strength constitute the dimensions of a representation that summarizes relative fighting capacity. Experiencing synchrony should therefore lead individuals to conceptualize an antagonist as smaller and weaker. We found that men who walked synchronously with a male confederate indeed envisioned a purported criminal as less physically formidable than did men who engaged in this task without synchronizing. PMID:25165456

  1. pK(a) determination of angiotensin II receptor antagonists (ARA II) by spectrofluorimetry.

    PubMed

    Cagigal, E; González, L; Alonso, R M; Jiménez, R M

    2001-10-01

    The acid-base equilibrium constants of a new family of antihypertensive drugs, the angiotensin II receptor antagonists (ARA II), Losartan, Irbesartan, Valsartan, Candesartan cilexetil, its metabolite Candesartan M1 and Telmisartan were determined by spectrofluorimetry. Relative fluorescent intensity (I(F,rel))-pH data were treated by graphical (derivatives and curve-fitting) and numerical methods (LETAGROP SPEFO). The resultant pK(a) values at an ionic strength of 0.5 M were (3.15+/-0.07) for Losartan, (4.70+/-0.06) for Irbesartan, (4.90+/-0.09) for Valsartan, (6.0+/-0.1) for Candesartan cilexetil, (3.9+/-0.1) for Candesartan M1, and (4.45+/-0.09) for Telmisartan.

  2. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation

    NASA Astrophysics Data System (ADS)

    Sneddon, Julie B.; Zhen, Hanson H.; Montgomery, Kelli; van de Rijn, Matt; Tward, Aaron D.; West, Robert; Gladstone, Hayes; Chang, Howard Y.; Morganroth, Greg S.; Oro, Anthony E.; Brown, Patrick O.

    2006-10-01

    Although tissue microenvironments play critical roles in epithelial development and tumorigenesis, the factors mediating these effects are poorly understood. In this work, we used a genomic approach to identify factors produced by cells in the microenvironment of basal cell carcinoma (BCC) of the skin, one of the most common human cancers. The global gene expression programs of stromal cell cultures derived from human BCCs showed consistent, systematic differences from those derived from nontumor skin. The gene most consistently expressed at a higher level in BCC tumor stromal cells compared with those from nontumor skin was GREMLIN 1, which encodes a secreted antagonist of the bone morphogenetic protein (BMP) pathway. BMPs and their antagonists are known to play a crucial role in stem and progenitor cell biology as regulators of the balance between expansion and differentiation. Consistent with the hypothesis that BMP antagonists might have a similar role in cancer, we found GREMLIN 1 expression in the stroma of human BCC tumors but not in normal skin in vivo. Furthermore, BMP 2 and 4 are expressed by BCC cells. Ex vivo, BMP inhibits, and Gremlin 1 promotes, proliferation of cultured BCC cells. We further found that GREMLIN 1 is expressed by stromal cells in many carcinomas but not in the corresponding normal tissue counterparts that we examined. Our data suggest that BMP antagonists may be important constituents of tumor stroma, providing a favorable microenvironment for cancer cell survival and expansion in many cancers. cancer biology | stem cell regulation | tissue microenvironment | tumor stroma

  3. Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro

    PubMed Central

    Zhang, Qiao; Wang, Shifeng; Yu, Yangyang; Sun, Shengnan; Zhang, Yuxin; Zhang, Yanling; Yang, Wei; Li, Shiyou; Qiao, Yanjiang

    2016-01-01

    Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 µM in the HEK293/ETAR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR. PMID:27490540

  4. CCK2 receptor antagonists: pharmacological tools to study the gastrin-ECL cell-parietal cell axis.

    PubMed

    Håkanson, R; Ding, X Q; Norlén, P; Lindström, E

    1999-03-17

    Gastrin-recognizing CCK2 receptors are expressed in parietal cells and in so-called ECL cells in the acid-producing part of the stomach. ECL cells are endocrine/paracrine cells that produce and store histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. The ECL cells are the principal cellular transducer of the gastrin-acid signal. Activation of the CCK2 receptor results in mobilization of histamine (and pancreastatin) from the ECL cells with consequent activation of the parietal cell histamine H2 receptor. Thus, release of ECL-cell histamine is a key event in the process of gastrin-stimulated acid secretion. The oxyntic mucosal histidine decarboxylase (HDC) activity and the serum pancreastatin concentration are useful markers for the activity of the gastrin-ECL cell axis. Powerful and selective CCK2 receptor antagonits have been developed from a series of benzodiazepine compounds. These agents are useful tools to study how gastrin controls the ECL cells. Conversely, the close control of ECL cells by gastrin makes the gastrin-ECL cell axis well suited for evaluating the antagonistic potential of CCK2 receptor antagonists with the ECL-cell HDC activity as a notably sensitive and reliable parameter. The CCK2 receptor antagonists YF476, YM022, RP73870, JB93182 and AG041R were found to cause prompt inhibition of ECL-cell histamine and pancreastatin secretion and synthesis. The circulating pancreastatin concentration is raised, was lowered when the action of gastrin on the ECL cells was blocked by the CCK2 receptor antagonists. These effects were associated with inhibition of gastrin-stimulated acid secretion. In addition, sustained receptor blockade was manifested in permanently decreased oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and CGA mRNA concentrations. CCK2 receptor blockade also induced hypergastrinemia, which probably reflects the impaired gastric acid secretion (no acid feedback inhibition of gastrin release

  5. Inhibition of establishment of primary and micrometastatic tumors by a urokinase plasminogen activator receptor antagonist.

    PubMed

    Ignar, D M; Andrews, J L; Witherspoon, S M; Leray, J D; Clay, W C; Kilpatrick, K; Onori, J; Kost, T; Emerson, D L

    1998-01-01

    Tumor establishment and metastasis are dependent on extracellular matrix proteolysis, tumor cell migration, and angiogenesis. Urokinase plasminogen activator (uPA) and its receptor are essential mediators of these processes. The purpose of this study was to investigate the effect of a recombinant human uPAR antagonist on growth, establishment, and metastasis of tumors derived from human cancer cell lines. A noncatalytic recombinant protein, consisting of amino acids 1-137 of human uPA and the CH2 and CH3 regions of mouse IgG1 (uPA-IgG), was expressed, purified, and shown to bind specifically to human uPAR and to saturate the surface of human tumor cells which express uPAR. Daily i.p. administration of uPA-IgG to nude mice extended latencies of unstaged tumors derived from Lox melanoma and SW48 colon carcinoma cells by 7.7 and 5.5 days, respectively. uPA-IgG treatment did not affect the growth of Lox or KB tumors staged to 200 mg before antagonist treatment commenced. The effect of uPA-IgG on the establishment of micrometastases was assessed in SCID mice. KB head/neck tumor cells were injected in the tail vein and allowed to seed for 48 h before initiation of daily i.p. injections of uPA-IgG for 24 days. The number of lung colonies ranged between 5 and 30% of vehicle-treated mice in two separate experiments. Furthermore, a single 800 microg dose of uPA-IgG administered 1 h prior to tail vein injection of KB cells reduced lung colony formation to just 3.5% of vehicle-treated SCID mice. These data demonstrate that antagonism of uPAR arrested metastasis and inhibited the establishment of primary tumors and micrometastases. Thus, small molecule uPAR antagonists may serve as useful adjuvant agents in combination with existing cancer chemotherapy.

  6. Recent Progress in the Use of Glucagon and Glucagon Receptor Antago-nists in the Treatment of Diabetes Mellitus

    PubMed Central

    Lotfy, Mohamed; Kalasz, Huba; Szalai, Gyorgy; Singh, Jaipaul; Adeghate, Ernest

    2014-01-01

    Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques. PMID:25674162

  7. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial

    PubMed Central

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri LH; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2014-01-01

    Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time. PMID:24569690

  8. Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

    PubMed Central

    Sharov, Andrey A.; Mardaryev, Andrei N.; Sharova, Tatyana Y.; Grachtchouk, Marina; Atoyan, Ruzanna; Byers, H. Randolph; Seykora, John T.; Overbeek, Paul; Dlugosz, Andrzej; Botchkarev, Vladimir A.

    2009-01-01

    Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways. PMID:19700758

  9. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial.

    PubMed

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri L H; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2014-05-01

    Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.

  10. Derivative chameleons

    SciTech Connect

    Noller, Johannes

    2012-07-01

    We consider generalized chameleon models where the conformal coupling between matter and gravitational geometries is not only a function of the chameleon field φ, but also of its derivatives via higher order co-ordinate invariants (such as ∂{sub μ}φ∂{sup μ}φ,□φ,...). Specifically we consider the first such non-trivial conformal factor A(φ,∂{sub μ}φ∂{sup μ}φ). The associated phenomenology is investigated and we show that such theories have a new generic mass-altering mechanism, potentially assisting the generation of a sufficiently large chameleon mass in dense environments. The most general effective potential is derived for such derivative chameleon setups and explicit examples are given. Interestingly this points us to the existence of a purely derivative chameleon protected by a shift symmetry for φ → φ+c. We also discuss potential ghost-like instabilities associated with mass-lifting mechanisms and find another, mass-lowering and instability-free, branch of solutions. This suggests that, barring fine-tuning, stable derivative models are in fact typically anti-chameleons that suppress the field's mass in dense environments. Furthermore we investigate modifications to the thin-shell regime and prove a no-go theorem for chameleon effects in non-conformal geometries of the disformal type.

  11. Derivative chameleons

    NASA Astrophysics Data System (ADS)

    Noller, Johannes

    2012-07-01

    We consider generalized chameleon models where the conformal coupling between matter and gravitational geometries is not only a function of the chameleon field phi, but also of its derivatives via higher order co-ordinate invariants (such as ∂μphi∂μphi,squphi,...). Specifically we consider the first such non-trivial conformal factor A(phi,∂μphi∂μphi). The associated phenomenology is investigated and we show that such theories have a new generic mass-altering mechanism, potentially assisting the generation of a sufficiently large chameleon mass in dense environments. The most general effective potential is derived for such derivative chameleon setups and explicit examples are given. Interestingly this points us to the existence of a purely derivative chameleon protected by a shift symmetry for phi → phi+c. We also discuss potential ghost-like instabilities associated with mass-lifting mechanisms and find another, mass-lowering and instability-free, branch of solutions. This suggests that, barring fine-tuning, stable derivative models are in fact typically anti-chameleons that suppress the field's mass in dense environments. Furthermore we investigate modifications to the thin-shell regime and prove a no-go theorem for chameleon effects in non-conformal geometries of the disformal type.

  12. Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists

    PubMed Central

    Zhang, Meng-Qi; Zhang, Xiao-Le; Li, Yan; Fan, Wen-Jia; Wang, Yong-Hua; Hao, Ming; Zhang, Shu-Wei; Ai, Chun-Zhi

    2011-01-01

    MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson’s disease and schizophrenia. Herein, we report the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [3H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q2 of 0.513, R2 ncv of 0.868, R2 pred = 0.876, while the CoMSIA model yielded a Q2 of 0.450, R2 ncv = 0.899, R2 pred = 0.735. For activity II study, CoMFA model yielded statistics of Q2 = 0.5, R2 ncv = 0.715, R2 pred = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R7, R3 and position A benefit activity I of the antagonists, but decrease it when projected in R8 and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3

  13. Lead Optimization Studies of Cinnamic Amide EP2 Antagonists

    PubMed Central

    2015-01-01

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  14. Lead optimization studies of cinnamic amide EP2 antagonists.

    PubMed

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.

  15. Therapeutic antagonists and conformational regulation of integrin function.

    PubMed

    Shimaoka, Motomu; Springer, Timothy A

    2003-09-01

    Integrins are a structurally elaborate family of adhesion molecules that transmit signals bi-directionally across the plasma membrane by undergoing large-scale structural rearrangements. By regulating cell-cell and cell-matrix contacts, integrins participate in a wide range of biological processes, including development, tissue repair, angiogenesis, inflammation and haemostasis. From a therapeutic standpoint, integrins are probably the most important class of cell-adhesion receptors. Recent progress in the development of integrin antagonists has resulted in their clinical application and has shed new light on integrin biology. On the basis of their mechanism of action, small-molecule integrin antagonists fall into three different classes. Each of these classes affect the equilibria that relate integrin conformational states, but in different ways.

  16. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

  17. Antagonists of Plant-parasitic Nematodes in Florida Citrus

    PubMed Central

    Walter, David Evans; Kaplan, David T.

    1990-01-01

    In a survey of antagonists of nematodes in 27 citrus groves, each with a history of Tylenchulus semipenetrans infestation, and 17 noncitrus habitats in Florida, approximately 24 species of microbial antagonists capable of attacking vermiform stages of Radopholus citrophilus were recovered. Eleven of these microbes and a species of Pasteuria also were observed attacking vermiform stages of T. semipenetrans. Verticillium chlamydosporium, Paecilomyces lilacinus, P. marquandii, Streptomyces sp., Arthrobotrys oligospora, and Dactylella ellipsospora were found infecting T. semipenetrans egg masses. Two species of nematophagous amoebae, five species of predatory nematodes, and 29 species of nematophagous arthropods also were detected. Nematode-trapping fungi and nematophagous arthropods were common inhabitants of citrus groves with a history of citrus nematode infestation; however, obligate parasites of nematodes were rare. PMID:19287759

  18. Antagonistic otolith-visual units in cat vestibular nuclei

    NASA Technical Reports Server (NTRS)

    Daunton, Nancy G.; Christensen, Carol A.

    1992-01-01

    The nature of neural coding of visual (Vis) and vestibular (Vst) information on translational motion in the region of the vestibular nuclei was investigated using extracellular single-unit recordings in alert adult cats. Responses were recorded and averaged over 60 cycles of stimulation in the vertical and horizontal planes, which included the Vst (movement of the animal in the dark), Vis (movement within lighted visual surround), and combined Vis and Vst (movement of the animal within the lighted stationary visual surround). Data are reported on responses to stimulations along the axis showing maximal sensitivity. A small number of units were identified that showed an antagonistic relationship between their Vis and Vst responses (since they were maximally excited by Vis and by Vst stimulations in the same direction). Results suggest that antagonistic units may belong to an infrequently encountered, but functionally distinct, class of neurons.

  19. Antagonists of Plant-parasitic Nematodes in Florida Citrus.

    PubMed

    Walter, D E; Kaplan, D T

    1990-10-01

    In a survey of antagonists of nematodes in 27 citrus groves, each with a history of Tylenchulus semipenetrans infestation, and 17 noncitrus habitats in Florida, approximately 24 species of microbial antagonists capable of attacking vermiform stages of Radopholus citrophilus were recovered. Eleven of these microbes and a species of Pasteuria also were observed attacking vermiform stages of T. semipenetrans. Verticillium chlamydosporium, Paecilomyces lilacinus, P. marquandii, Streptomyces sp., Arthrobotrys oligospora, and Dactylella ellipsospora were found infecting T. semipenetrans egg masses. Two species of nematophagous amoebae, five species of predatory nematodes, and 29 species of nematophagous arthropods also were detected. Nematode-trapping fungi and nematophagous arthropods were common inhabitants of citrus groves with a history of citrus nematode infestation; however, obligate parasites of nematodes were rare.

  20. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    PubMed

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

  1. Optimization of amide-based EP3 receptor antagonists.

    PubMed

    Lee, Esther C Y; Futatsugi, Kentaro; Arcari, Joel T; Bahnck, Kevin; Coffey, Steven B; Derksen, David R; Kalgutkar, Amit S; Loria, Paula M; Sharma, Raman

    2016-06-01

    Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc.2007, 6, 881; (b) Annu. Rep. Med. Chem.2010, 45, 380).

  2. Exploration of a new series of PAR1 antagonists.

    PubMed

    Planty, Bruno; Pujol, Chantal; Lamothe, Marie; Maraval, Catherine; Horn, Clemens; Le Grand, Bruno; Perez, Michel

    2010-03-01

    Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25mpk iv for compound 30.

  3. Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer

    PubMed Central

    Yuan, Kaiyu; Yong, Sun; Xu, Fei; Zhou, Tong; McDonald, Jay M; Chen, Yabing

    2015-01-01

    Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between −295 to −300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy. PMID:26320171

  4. Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

    DTIC Science & Technology

    2014-09-01

    until animals performed the water maze tests. SLEEP DEPRIVATION PROCEDURES Animals were sleep deprived (SD) from ZT12-18 by progressive manual... sleep and performance , and the effects of these compounds on biomarkers associated with normal sleep . BODY Task 2. Test the hypothesis that...antagonist almorexant promotes sleep without impairment of performance in rats" was published in Frontiers in Neuroscience in January, 2014. Progress

  5. Systemic Mineralocorticoid Antagonists in the Treatment of Central Serous Chorioretinopathy.

    PubMed

    Yang, Dong; Eliott, Dean

    2017-01-01

    Central serous chorioretinopathy (CSCR) is a challenging disease characterized by subretinal serous fluid accumulation. The complex pathogenesis is still not fully understood, but is thought to be multifactorial and involves exogenous and endogenous factors affecting the choroid and retinal pigment epithelium. The involvement of corticosteroids is undisputed, while the contribution of mineralocorticoid pathways is under investigation. This review addresses the proposed pathogenesis models and the evidence for systemic treatment of CSCR with mineralocorticoid antagonists.

  6. Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

    PubMed Central

    2012-01-01

    A hallmark pathological feature of the Alzheimer’s disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD. PMID:23173073

  7. Discovery of new muscarinic acetylcholine receptor antagonists from Scopolia tangutica

    PubMed Central

    Du, Nana; Liu, Yanfang; Zhang, Xiuli; Wang, Jixia; Zhao, Jianqiang; He, Jian; Zhou, Han; Mei, Lijuan; Liang, Xinmiao

    2017-01-01

    Scopolia tangutica (S. tangutica) is a traditional Chinese medicinal plant used for antispasmodics, anesthesia, analgesia and sedation. Its pharmacological activities are mostly associated with the antagonistic activity at muscarinic acetylcholine receptors (mAchRs) of several known alkaloids such as atropine and scopolamine. With our recent identification of four hydroxycinnamic acid amides from S. tangutica, we hypothesized that this plant may contain previously unidentified alkaloids that may also contribute to its in vivo effect. Herein, we used a bioassay-guided multi-dimension separation strategy to discover novel mAchR antagonists from S. tangutica. The core of this approach is to use label-free cell phenotypic assay to first identify active fractions, and then to guide purification of active ligands. Besides four tropanes and six cinnamic acid amides that have been previously isolated from S. tangutica, we recently identified two new tropanes, one new cinnamic acid amide, and nine other compounds. Six tropane compounds purified from S. tangutica for the first time were confirmed to be competitive antagonists of muscarinic receptor 3 (M3), including the two new ones 8 and 12 with IC50 values of 1.97 μM and 4.47 μM, respectively. Furthermore, the cinnamic acid amide 17 displayed 15-fold selectivity for M1 over M3 receptors. These findings will be useful in designing lead compounds for mAchRs and elucidating mechanisms of action of S. tangutica. PMID:28387362

  8. Synergistic and antagonistic drug combinations depend on network topology.

    PubMed

    Yin, Ning; Ma, Wenzhe; Pei, Jianfeng; Ouyang, Qi; Tang, Chao; Lai, Luhua

    2014-01-01

    Drug combinations may exhibit synergistic or antagonistic effects. Rational design of synergistic drug combinations remains a challenge despite active experimental and computational efforts. Because drugs manifest their action via their targets, the effects of drug combinations should depend on the interaction of their targets in a network manner. We therefore modeled the effects of drug combinations along with their targets interacting in a network, trying to elucidate the relationships between the network topology involving drug targets and drug combination effects. We used three-node enzymatic networks with various topologies and parameters to study two-drug combinations. These networks can be simplifications of more complex networks involving drug targets, or closely connected target networks themselves. We found that the effects of most of the combinations were not sensitive to parameter variation, indicating that drug combinational effects largely depend on network topology. We then identified and analyzed consistent synergistic or antagonistic drug combination motifs. Synergistic motifs encompass a diverse range of patterns, including both serial and parallel combinations, while antagonistic combinations are relatively less common and homogenous, mostly composed of a positive feedback loop and a downstream link. Overall our study indicated that designing novel synergistic drug combinations based on network topology could be promising, and the motifs we identified could be a useful catalog for rational drug combination design in enzymatic systems.

  9. [5-HT3 receptor antagonist als analgetics in rheumatic diseases].

    PubMed

    Müller, W; Fiebich, B L; Stratz, T

    2006-10-01

    Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.

  10. The complex roles of Wnt antagonists in RCC.

    PubMed

    Saini, Sharanjot; Majid, Shahana; Dahiya, Rajvir

    2011-10-25

    Renal cell carcinoma (RCC) is the most lethal of all the genitourinary cancers, as it is generally refractory to current treatment regimens, including chemotherapy and radiation therapy. Targeted therapies against critical signaling pathways associated with RCC pathogenesis, such as vascular endothelial growth factor, von Hippel-Lindau tumor suppressor and mammalian target of rapamycin, have shown limited efficacy so far. Thus, Wnt signaling, which is known to be intricately involved in the pathogenesis of RCC, has attracted much interest. Several Wnt signaling components have been examined in RCC, and, while studies suggest that Wnt signaling is constitutively active in RCC, the molecular mechanisms differ considerably from other human carcinomas. Increasing evidence indicates that secreted Wnt antagonists have important roles in RCC pathogenesis. Considering these vital roles, it has been postulated--and supported by experimental evidence--that the functional loss of Wnt antagonists, for example by promoter hypermethylation, can contribute to constitutive activation of the Wnt pathway, resulting in carcinogenesis through dysregulation of cell proliferation and differentiation. However, subsequent functional studies of these Wnt antagonists have demonstrated the inherent complexities underlying their role in RCC pathogenesis.

  11. μ Opioid receptor: novel antagonists and structural modeling

    PubMed Central

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-01-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates. PMID:26888328

  12. Effects of two antagonistic ecosystem engineers on infaunal diversity

    NASA Astrophysics Data System (ADS)

    González-Ortiz, V.; Alcazar, P.; Vergara, J. J.; Pérez-Lloréns, J. L.; Brun, F. G.

    2014-02-01

    The role of ecosystem engineers has been highlighted in recent decades because of their importance for ecosystem functioning, although the interaction between different antagonistic engineer species and their effects on ecosystems have been so far poorly investigated. Coastal areas are good natural laboratories to explore such interactions, since they are often inhabited by macrophyte beds (autogenic engineers) and bioturbator species (allogenic engineers) with antagonistic effects on ecosystem properties and processes (e.g. species diversity, nutrient fluxes, etc.). The main goal of this study was to determine how coexisting antagonistic ecosystem engineers could influence benthic diversity and available resources in soft-bottom areas. To achieve this goal, a two-month experiment was carried out in situ by introducing artificial seagrass patches in a soft-bottom area inhabited by the fiddler crab Uca tangeri. Both the experimental exclusion of burrows as well as the presence of artificial seagrass-like structures (mimics) resulted in higher macrobenthic density and species richness in the benthic community. Resource availability for organisms (sediment chlorophyll a and epiphytes) was also favoured by the presence of mimics. Therefore, the higher structural complexity (above- and below-ground) associated with seagrass mimics promoted positive effects for infauna such as creation of a new habitat ready to colonize, reduction of the crab burrowing activity and the enhancement of resource availability, which resulted in increased diversity in the benthic community.

  13. μ Opioid receptor: novel antagonists and structural modeling

    NASA Astrophysics Data System (ADS)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  14. Antagonistic interaction networks among bacteria from a cold soil environment.

    PubMed

    Prasad, Sathish; Manasa, Poorna; Buddhi, Sailaja; Singh, Shiv Mohan; Shivaji, Sisinthy

    2011-11-01

    Microbial antagonism in an Arctic soil habitat was demonstrated by assessing the inhibitory interactions between bacterial isolates from the same location. Of 139 isolates obtained from five soil samples, 20 antagonists belonging to the genera, Arthrobacter, Pseudomonas and Flavobacterium were identified. Inter-genus, inter-species and inter-strain antagonism was observed between the interacting members. The extent of antagonism was temperature dependent. In some cases, antagonism was enhanced at 4 °C but suppressed at 18 °C while in some the reverse phenomenon was observed. To interpret antagonism from an ecological perspective, the interacting members were delineated according to their positional roles in a theoretical antagonistic network. When only one antimicrobial producer (P) was present, all the other members permitted grouping into either sensitive (S) or resistant (R). Composite interactive types such as PSR, PS, PR or SR could be designated only when at least two producers were present. Mapping of all possible antagonistic interaction networks based on the individual positional roles of the interactive types illustrates the existence of complex and interconnected networks among microbial communities.

  15. Newer calcium channel antagonists and the treatment of hypertension.

    PubMed

    Cummins, D F

    1999-07-01

    Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.

  16. The effects of histamine H3-receptor antagonists on amygdaloid kindled seizures in rats.

    PubMed

    Kakinoki, H; Ishizawa, K; Fukunaga, M; Fujii, Y; Kamei, C

    1998-07-15

    The effects of histamine H3-receptor antagonists, thioperamide, and clobenpropit on amygdaloid kindled seizures were investigated in rats. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injections of H3-antagonists resulted in a dose-related inhibition of amygdaloid kindled seizures. An inhibition induced by thioperamide was antagonized by an H3-agonist [(R)-alpha-methylhistamine] and H1-antagonists (diphenhydramine and chlorpheniramine). On the other hand, an H2-antagonist (cimetidine and ranitidine) caused no antagonistic effect. Metoprine, an inhibitor of N-methyltransferase was also effective in inhibiting amygdaloid kindled seizure, and this effect was augmented by thioperamide treatment.

  17. Complex derivatives

    NASA Astrophysics Data System (ADS)

    Battiston, Stefano; Caldarelli, Guido; Georg, Co-Pierre; May, Robert; Stiglitz, Joseph

    2013-03-01

    The intrinsic complexity of the financial derivatives market has emerged as both an incentive to engage in it, and a key source of its inherent instability. Regulators now faced with the challenge of taming this beast may find inspiration in the budding science of complex systems.

  18. Arginine mimetic structures in biologically active antagonists and inhibitors.

    PubMed

    Masic, Lucija Peterlin

    2006-01-01

    Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the

  19. Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease.

    PubMed

    della Rovere, F; Broccio, M; Granata, A; Zirilli, A; Brugnano, L; Artemisia, A; Broccio, G

    1996-01-01

    The blood of the subjects suffering from Neoplastic Disease (ND) shows phenomena of membrane peroxidation due to the presence of Free Radicals (FRs), in a quantity much greater than the one observed in the blood of healthy subjects. This can be detected either by calculating the time necessary for the formation of "Heinz bodies" (Hbs), (p < 0.00001) after oxidative stress of the blood in vitro with acetylphenylidrazine (APH), or by calculating the methemoglobin (metHb) quantity that forms after the same treatment (P < 0.00001). The statistical analyses we carried out showed that metHb formation was not affected by age, sex, smoking habits, red blood cell number, Hb, Ht or tumor staging. In this study, by using equal parameters of investigation, we noted that the blood of the subjects with ND who were previously treated with calcium-antagonists drugs and with antagonists of H1 and H2 receptors, gave results completely superimposable on the results obtained from healthy subjects, implying that the treatment had avoided the increase of FRs. Therefore we concluded that calcium-antagonists and the antagonists of the H1 and H2 receptors behave as antioxidant substances, having decreased the FRs damaging activity on the cellular membranes, thus controlling, although to a limited degree, the pejorative evolution of the disease. It is also important to remember that investigations into the ND, even possible screenings, must take into account the above said data, submitting the subjects under investigation to a pharmacological wash out, particularly with those substances which, are considered to be scavengers of FRs. Some of these substances are investigated in this work.

  20. Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists.

    PubMed

    Pasternak, Alexander; Goble, Stephen D; Doss, George A; Tsou, Nancy N; Butora, Gabor; Vicario, Pasquale P; Ayala, Julia Marie; Struthers, Mary; Demartino, Julie A; Mills, Sander G; Yang, Lihu

    2008-02-15

    In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.

  1. Apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine for adenosine A1 and A2 receptors in isolated tissues from guinea-pigs.

    PubMed Central

    Collis, M. G.; Stoggall, S. M.; Martin, F. M.

    1989-01-01

    1. The classification of adenosine receptor subtypes (A1 and A2) in intact tissues has been based on the order of agonist potency. In this study the apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine (CPX), an antagonist which has been reported to be A1 selective, and the non-selective antagonist 1,3-dimethyl-8-phenylxanthine (8PT) has been evaluated on isolated tissues from the guinea-pig. 2. The isolated tissues used were atria (bradycardic response, proposed A1 sub-type), aorta and trachea (relaxant response, proposed A2 sub-type). 3. Both the xanthines antagonized responses to adenosine in the three tissues but had little or no effect on responses to carbachol (atria), sodium nitrite (aorta) or isoprenaline (trachea). 4. pA2 values for 8PT were similar on the three tissues (6.3-6.7), however, the pA2 value for CPX on the atria (7.9-8.4) was greater than that on the aorta (6.6) or trachea (6.6). 5. These results support the suggestion that the adenosine receptors which mediate bradycardia in the atrium are of the A1 sub-type and that those which mediate relaxation in the aorta and trachea are of the A2 type. PMID:2790383

  2. Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925.

    PubMed

    Rafehi, Muhammad; Burbiel, Joachim C; Attah, Isaac Y; Abdelrahman, Aliaa; Müller, Christa E

    2017-03-01

    The Gq protein-coupled, ATP- and UTP-activated P2Y2 receptor is a potential drug target for a range of different disorders, including tumor metastasis, inflammation, atherosclerosis, kidney disorders, and osteoporosis, but pharmacological studies are impeded by the limited availability of suitable antagonists. One of the most potent and selective antagonists is the thiouracil derivative AR-C118925. However, this compound was until recently not commercially available and little is known about its properties. We therefore developed an improved procedure for the synthesis of AR-C118925 and two derivatives to allow up-scaling and assessed their potency in calcium mobilization assays on the human and rat P2Y2 receptors recombinantly expressed in 1321N1 astrocytoma cells. The compound was further evaluated for inhibition of P2Y2 receptor-induced β-arrestin translocation. AR-C118925 behaved as a competitive antagonist with pA 2 values of 37.2 nM (calcium assay) and 51.3 nM (β-arrestin assay). Selectivity was assessed vs. related receptors including P2X, P2Y, and adenosine receptor subtypes, as well as ectonucleotidases. AR-C118925 showed at least 50-fold selectivity against the other investigated targets, except for the P2X1 and P2X3 receptors which were blocked by AR-C118925 at concentrations of about 1 μM. AR-C118925 is soluble in buffer at pH 7.4 (124 μM) and was found to be metabolically highly stable in human and mouse liver microsomes. In Caco2 cell experiments, the compound displayed moderate permeability indicating that it may show limited peroral bioavailability. AR-C118925 appears to be a useful pharmacological tool for in vitro and in vivo studies.

  3. A non-peptide NK1-receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically.

    PubMed Central

    Moussaoui, S. M.; Montier, F.; Carruette, A.; Blanchard, J. C.; Laduron, P. M.; Garret, C.

    1993-01-01

    1. The non-peptide neurokinin NK1-receptor antagonist, RP 67580 (3aR, 7aR), a perhydroisoindolone derivative, powerfully reduced plasma extravasation in rat hind paw skin induced by local application of xylene (ID50 = 0.03 mg kg-1, i.v.) or capsaicin (ID50 = 0.06 mg kg-1, i.v.), or by i.v. injection of exogenous substance P (SP) or septide ([pGlu6,Pro9]SP(6-11)) (ID50 = 0.04-0.05 mg kg-1, i.v.). RP 67580 (1 mg kg-1, i.v.) also abolished capsaicin-induced nasal fluid hypersecretion (by 82 +/- 5%). These effects were found to be stereospecific, the enantiomer, RP 68651 (3aS, 7aS), being inactive at 1 mg kg-1, i.v. 2. In rats neonatally treated with capsaicin (50 mg kg-1, s.c.), plasma extravasation induced by SP was significantly increased (by 43 +/- 7%). RP 67580 (1 mg kg-1, i.v.) completely inhibited the SP-induced plasma extravasation in capsaicin neonatally treated-animals, as it did in control animals. This result suggests that RP 67580 acts at the postsynaptic level for the inhibition of plasma extravasation. 3. Opioid receptor agonists, mu-(morphine) and kappa-(PD-117302) at 10 mg kg-1, s.c., in contrast to NK1-receptor antagonists, did not inhibit plasma extravasation induced by exogenous SP. They were, however, partially effective against plasma extravasation induced by electrical nerve stimulation (74 +/- 4% and 48 +/- 9% inhibition at 10 mg kg-1, s.c. of morphine and PD-117302, respectively, compared to 90 +/- 3% inhibition obtained with RP 67580, 3 mg kg-1, s.c.).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7684305

  4. Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate.

    PubMed

    Heyne, Galen W; Melberg, Cal G; Doroodchi, Padydeh; Parins, Kia F; Kietzman, Henry W; Everson, Joshua L; Ansen-Wilson, Lydia J; Lipinski, Robert J

    2015-01-01

    The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in "non-syndromic" orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.

  5. A novel small-molecule enantiomeric analogue of traditional (-)-morphinans has specific TLR9 antagonist properties and reduces sterile inflammation-induced organ damage.

    PubMed

    Hoque, Rafaz; Farooq, Ahmad; Malik, Ahsan; Trawick, Bobby N; Berberich, David W; McClurg, Joseph P; Galen, Karen P; Mehal, Wajahat

    2013-04-15

    TLR9 is a key determinant of the innate immune responses in both infectious and sterile injury. Specific antagonism of TLR9 is of great clinical interest to reduce tissue damage in a wide range of pathologies, and has been approached by modification of nucleic acids, the recognized ligand for TLR9. Such oligonucleotide-derived pharmacotherapeutics have limitations in specificity for nucleic acid receptors, significant potential for immunologic recognition with generation of innate and adaptive immune responses, and limited bioavailability. We have identified enantiomeric analogues of traditional (-)-morphinans as having TLR9 antagonist properties on reporter cell lines. One of these analogues (COV08-0064) is demonstrated to be a novel small-molecule antagonist of TLR9 with greater specificity for TLR9 than oligo-based antagonists. COV08-0064 has wide bioavailability, including the s.c. and oral routes. It specifically inhibits the action of TLR9 antagonists on reporter cells lines and the production of cytokines by TLR9 agonists from primary cells. It also has efficacy in limiting TLR9-mediated sterile inflammation in in vivo models of acute liver injury and acute pancreatitis. The identification of a morphinan-based novel small-molecule structure with TLR9 antagonism is a significant step in expanding therapeutic strategies in the field of sterile inflammatory injury.

  6. An inhibitor of apoptosis protein antagonist T-3256336 potentiates the antitumor efficacy of the Nedd8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924).

    PubMed

    Sumi, Hiroyuki; Inazuka, Masakazu; Morimoto, Megumi; Hibino, Ryosuke; Hashimoto, Kentaro; Ishikawa, Tomoyasu; Kuida, Keisuke; Smith, Peter G; Yoshida, Sei; Yabuki, Masato

    2016-11-18

    Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFα-neutralizing antibody. In the present mechanistic analyses, pevonedistat induced TNFα mRNA and triggered IAP antagonist-dependent extrinsic apoptotic cell death in cancer cell lines. Furthermore, synergistic effects of the combination of T-3256336 and pevonedistat were demonstrated in a HL-60 mouse xenograft model. Our findings provide mechanistic evidence of the effects of IAP antagonists in combination with NAE inhibitors, and demonstrate the potential of a new combination therapy for cancer.

  7. A Novel Small Molecule Enantiomeric Analogue of Traditional (−)-morphinans has Specific TLR9 Antagonist Properties and Reduces Sterile Inflammation Induced Organ Damage

    PubMed Central

    Hoque, Rafaz; Farooq, Ahmad; Malik, Ahsan; Trawick, Bobby N.; Berberich, David W.; McClurg, Joseph P.; Galen, Karen P.; Mehal, Wajahat

    2013-01-01

    TLR9 is a key determinant of the innate immune responses in both infectious and sterile injury. Specific antagonism of TLR9 is of great clinical interest to reduce tissue damage in a wide range of pathologies, and has been approached by modification of nucleic acids, the recognized ligand for TLR9. Such oligonucleotide-derived pharmacotherapeutics have limitations in specificity for nucleic acid receptors, significant potential for immunologic recognition with generation of innate and adaptive immune responses, and limited bioavailability. We have identified enantiomeric analogues of traditional (−)-morphinans as having TLR9 antagonist properties on reporter cell lines. One of these analogues (COV08-0064) is demonstrated to be a novel small molecule antagonist of TLR9 with greater specificity for TLR9 than oligo based antagonists. COV08-0064 has wide bioavailability, including the subcutaneous and per oral route. It specifically inhibits the action of TLR9 antagonists on reporter cells lines and the production of cytokines by TLR9 agonists from primary cells. It also has efficacy in limiting TLR9 mediated sterile inflammation in in vivo models of acute liver injury and acute pancreatitis. The identification of a morphinan based novel small molecule structure with TLR9 antagonism is a significant step in expanding therapeutic strategies in the field of sterile inflammatory injury. PMID:23509352

  8. Classification and virtual screening of androgen receptor antagonists.

    PubMed

    Li, Jiazhong; Gramatica, Paola

    2010-05-24

    Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

  9. Cardiovascular effects of ghrelin antagonist in conscious rats.

    PubMed

    Vlasova, Maria A; Järvinen, Kristiina; Herzig, Karl-Heinz

    2009-08-07

    Ghrelin, a 28 aa growth-hormone-releasing peptide, has been shown to increase food intake and decrease arterial pressure in animals and in humans. Recently, a ghrelin antagonist (GhA), [d-Lys-3]-GHRP-6, was demonstrated to decrease food intake in mice, but its cardiovascular actions have not been described. In the present study, the effects of the GhA on cardiovascular parameters in conscious rats were investigated and the involvement of the sympathetic nervous system evaluated. Mean arterial pressure (MAP) and heart rate (HR) measurements were assessed by radiotelemetry. GhA was administered in doses of 2, 4 and 6 mg/kg subcutaneously (s.c.). MAP as well as HR was dose-dependently elevated after sc application of GhA. Sympathetic blockade of alpha-adrenoreceptors with phentolamine (3 mg/kg, s.c.) and simultaneous antagonism of beta(1)-adrenoreceptors with atenolol (10 mg/kg, s.c.) abolished the increase in MAP and HR induced by GhA (4 mg/kg, s.c.). Administration of phentolamine alone inhibited the increase of MAP, but not HR; atenolol alone abolished the elevation of both MAP and HR evoked by GhA. These results suggest that the peripheral injection of ghrelin antagonist increases arterial pressure and heart rate, at least in part, through the activation of the sympathetic nervous system. Therefore, the use of the ghrelin antagonist system as a therapeutic target for reduction in food intake might lead to serious side effects like elevated blood pressure in humans mostly already having an elevated blood pressure as part of their metabolic syndrome.

  10. Making safer preoperative arrangements for patients using vitamin K antagonists

    PubMed Central

    van Fessem, Joris; Willems, Jessica; Kruip, Marieke; Hoeks, Sanne; Jan Stolker, Robert

    2017-01-01

    Use of vitamin K antagonists creates a risk for patient health and safety. The Dutch framework “Nationwide Standard Integrated Care of Anticoagulation” propagates a shared plan and responsibility by surgeon and anesthesiologist together in the preoperative setting. In our institution, this framework had not been implemented. Therefore, a quality-improvement project was started at the Anesthesia Department to improve perioperative safety. After exploration of barriers, multiple interventions were carried out to encourage co-workers at the preoperative screening department to take shared responsibility: distribution of prints, adjustments in electronic patient records, introduction of a protocol and education sessions. Efficacy was measured retrospectively performing a before-after study collecting perioperative data of patients using vitamin K antagonists. The primary outcome measure was the percentage of predefined safe preoperative plans. Secondary outcome measures were (1) incidence of postoperative bleeding and thrombo-embolic events within the first 24 hours after intervention and (2) necessity to preoperative correction of anticoagulation. Before intervention 72 (29%) safe, 93 (38%) partially unsafe and 83 (33%) unsafe arrangements were made. After the intervention these numbers were 105 (80%), 23 (17%) en 4 (3%), respectively: a significant 51% increase in safe preoperative plans (P<0.001). We observed no significant difference (P=0.369) regarding bleeding and thrombo-embolic events: pre-intervention 12 (5%) cases of postoperative bleeding were documented, vs. 6 (5%) post intervention and the number of thrombo-embolic events was 5 (2%) vs. 0. Also, no significant differences concerning preoperative correction of anticoagulation were observed: 11 (4%) vs. 8 (6%) (P=0.489). This quality improvement project demonstrates a major improvement in safer preoperative arrangements in our institution regarding vitamin K antagonists, using the described interventions

  11. Sexually Antagonistic “Zygotic Drive” of the Sex Chromosomes

    PubMed Central

    Rice, William R.; Gavrilets, Sergey; Friberg, Urban

    2008-01-01

    Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic “zygotic drive”, because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic “arms race” between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans. PMID:19096519

  12. Short stature caused by a natural growth hormone antagonist.

    PubMed

    Chihara, K; Takahashi, Y; Kaji, H; Goji, K; Okimura, Y; Abe, H

    1998-01-01

    Severe short stature in a male child due to a single mutation in the GH-1 gene was first reported in 1996 by Takahashi et al. [N Engl J Med 1996;334:432-436]. This missense mutation was predicted to convert codon 77 from arginine (R) to cysteine (C). The child's chronological age was 4 years and 11 months, and his bone age 2 years and 6 months, i.e., equal to only 51% of his chronological age. Body proportions were normal except for the prominent forehead and saddle nose. Pituitary size was normal on magnetic resonance imaging examinations. Serum IGF-1, IGFBP-3 and GHBP were all decreased or at the lower limit of the normal range. Nocturnal urinary growth hormone (GH) excretion was high. Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one. The R77C mutant GH possessed a 6 times greater affinity to GHBP than the wild-type GH, and inhibited tyrosine phosphorylation in IM-9 cells 10 times more potently than the wild-type GH, showing an antagonistic or a dominant negative action. In agreement with the antagonistic property of the mutant GH exhibited, the child did not show any increase in serum IGF-1 levels after exogenous hGH administration. It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive, as in the patient we recently described elsewhere. Therefore, this patient's condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist.

  13. Non-vitamin K antagonist oral anticoagulants and heart failure.

    PubMed

    Isnard, Richard; Bauer, Fabrice; Cohen-Solal, Alain; Damy, Thibaud; Donal, Erwan; Galinier, Michel; Hagège, Albert; Jourdain, Patrick; Leclercq, Christophe; Sabatier, Rémi; Trochu, Jean-Noël; Cohen, Ariel

    2016-11-01

    Thromboembolism contributes to morbidity and mortality in patients with heart failure (HF), and atrial fibrillation (AF) is one of the main factors promoting this complication. As they share many risk factors, HF and AF frequently coexist, and patients with both conditions are at a particularly high risk of thromboembolism. Non-vitamin K antagonist oral anticoagulants (NOACs) are direct antagonists of thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban and edoxaban), and were designed to overcome the limitations of vitamin K antagonists. Compared with warfarin in non-valvular AF, NOACs demonstrated non-inferiority with better safety, most particularly for intracranial haemorrhages. Therefore, the European Society of Cardiology guidelines recommend NOACs for most patients with non-valvular AF. Subgroups of patients with both AF and HF from the pivotal studies investigating the safety and efficacy of NOACs have been analysed and, for each NOAC, results were similar to those of the total analysis population. A recent meta-analysis of these subgroups has confirmed the better efficacy and safety of NOACs in patients with AF and HF - particularly the 41% decrease in the incidence of intracranial haemorrhages. The prothrombotic state associated with HF suggests that patients with HF in sinus rhythm could also benefit from treatment with NOACs. However, in the absence of clinical trial data supporting this indication, current guidelines do not recommend anticoagulant treatment of patients with HF in sinus rhythm. In conclusion, recent analyses of pivotal studies support the use of NOACs in accordance with their indications in HF patients with non-valvular AF.

  14. Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

    PubMed

    Warawa, E J; Migler, B M; Ohnmacht, C J; Needles, A L; Gatos, G C; McLaren, F M; Nelson, C L; Kirkland, K M

    2001-02-01

    A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

  15. Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy

    PubMed Central

    Cho, Byung-Sik; Zeng, Zhihong; Mu, Hong; Wang, Zhiqiang; McQueen, Teresa; Protopopova, Marina; Cortes, Jorge; Marszalek, Joseph R.; Peng, Sheng-Bin; Ma, Wencai; Davis, R. Eric; Thornton, Donald E.; Andreeff, Michael

    2015-01-01

    Targeting the stromal cell–derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell–derived factor 1 (SDF-1)α–induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and β-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications. PMID:26031918

  16. SAR analysis of innovative selective small molecule antagonists of sphingosine-1-phosphate 4 (S1P₄) receptor.

    PubMed

    Urbano, Mariangela; Guerrero, Miguel; Zhao, Jian; Velaparthi, Subash; Schaeffer, Marie-Therese; Brown, Steven; Rosen, Hugh; Roberts, Edward

    2011-09-15

    Recent evidence suggests an innovative application of chemical modulators targeting the S1P(4) receptor as novel mechanism-based drugs for the treatment of influenza virus infection. Modulation of the S1P(4) receptor may also represent an alternative therapeutic approach for clinical conditions where reactive thrombocytosis is an undesired effect or increased megakaryopoiesis is required. With the exception of our recent research program disclosure, we are not aware of any selective S1P(4) antagonists reported in the literature to date. Herein, we describe complementary structure-activity relationships (SAR) of the high-throughput screening (HTS)-derived hit 5-(2,5-dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide and its 2,5-dimethylphenyl analog. Systematic structural modifications of the furan ring showed that both steric and electronic factors in this region have a significant impact on the potency. The furan moiety was successfully replaced with a thiophene or phenyl ring maintaining potency in the low nanomolar range and high selectivity against the other S1P receptor subtypes. By expanding the molecular diversity within the hit-derived class, our SAR study provides innovative small molecule potent and selective S1P(4) antagonists suitable for in vivo pharmacological validation of the target receptor.

  17. Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis.

    PubMed

    Song, Jeong Sup; Kang, Chun Mi; Kang, Hyeon Hui; Yoon, Hyung Kyu; Kim, Young Kyoon; Kim, Kwan Hyung; Moon, Hwa Sik; Park, Sung Hak

    2010-06-30

    CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1), has been shown to play a critical role in mobilizing the bone marrow (BM)-derived stem cells and inflammatory cells. We studied the effects of AMD3100, CXCR4 antagonist, on a murine bleomycin-induced pulmonary fibrosis model. Treatment of mice with AMD3100 in bleomycin-treated mice resulted in the decrease of SDF-1 in bronchoalveolar lavage (BAL) fluids at an early stage and was followed by the decrease of fibrocytes in the lung. AMD3100 treatment decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) and CXCR4 expression at the later stage (day 7 and 21) after bleomycin injury. The collagen content and pulmonary fibrosis were significantly attenuated by AMD3100 treatment in later stage of bleomycin injury. AMD3100 treatment also decreased the murine mesenchymal and hematopoietic stem cell chemotaxis when either in the stimulation with bleomycin treated lung lysates or SDF-1 in vitro. In BM stem cell experiments, the phosphorylation of p38 MAPK which was induced by SDF-1 was significantly blocked by addition of AMD3100. Our data suggest that AMD3100 might be effective in preventing the pulmonary fibrosis by inhibiting the fibrocyte mobilization to the injured lung via blocking the SDF-1/CXCR4 axis.

  18. Synthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists.

    PubMed

    Katayama, S; Ae, N; Nagata, R

    2001-05-18

    The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.

  19. Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists

    PubMed Central

    Wang, Yuwei; Han, Rui; Zhang, Huimin; Liu, Hongli; Liu, Huanxiang; Gramatica, Paola

    2017-01-01

    The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process. PMID:28293633

  20. Esthetic Prosthetic Restorations: Reliability and Effects on Antagonist Dentition

    PubMed Central

    Daou, Elie E.

    2015-01-01

    Recent advances in ceramics have greatly improved the functional and esthetic properties of restorative materials. New materials offer an esthetic and functional oral rehabilitation, however their impact on opposing teeth is not welldocumented. Peer-reviewed articles published till December 2014 were identified through Pubmed (Medline and Elsevier). Scientifically, there are several methods of measuring the wear process of natural dentition which enhances the comparison of the complicated results. This paper presents an overview of the newly used prosthetic materials and their implication on antagonist teeth or prostheses, especially emphasizing the behavior of zirconia restorations. PMID:26962376

  1. The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist.

    PubMed

    Halliday, C A; Jones, B J; Skingle, M; Walsh, D M; Wise, H; Tyers, M B

    1991-04-01

    1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

  2. Lymphocyte homing antagonists in the treatment of inflammatory bowel diseases.

    PubMed

    Saruta, Masayuki; Papadakis, Konstantinos A

    2014-09-01

    Lymphocyte homing antagonists represent promising therapeutic agents for the treatment of idiopathic inflammatory bowel disease (IBD). Several critical molecules involved in the recruitment of inflammatory cells in the intestine, including integrins and chemokine receptors, have been successfully targeted for the treatment of IBD. These agents have shown great promise for the induction and maintenance of remission for both Crohn disease and ulcerative colitis. This article discusses currently approved prototypic agents for the treatment of IBD (natalizumab, anti-α4 integrin; vedolizumab, anti-α4β7 integrin), and several other agents in the same class currently under development.

  3. Antagonistic action of pitrazepin on human and rat GABAA receptors

    PubMed Central

    Demuro, Angelo; Martinez-Torres, Ataulfo; Francesconi, Walter; Miledi, Ricardo

    1999-01-01

    Pitrazepin, 3-(piperazinyl-1)-9H-dibenz(c,f) triazolo(4,5-a)azepin is a piperazine antagonist of GABA in a variety of electrophysiological and in vitro binding studies involving GABA and glycine receptors. In the present study we have investigated the effects of pitrazepin, and the GABAA antagonist bicuculline, on membrane currents elicited by GABA in Xenopus oocytes injected with rat cerebral cortex mRNA or cDNAs encoding α1β2 or α1β2γ2S human GABAA receptor subunits.The three types of GABAA receptors expressed were reversibly antagonized by bicuculline and pitrazepin in a concentration-dependent manner. GABA dose-current response curves for the three types of receptors were shifted to the right, in a parallel manner, by increasing concentrations of pitrazepin.Schild analyses gave pA2 values of 6.42±0.62, n=4, 6.41±1.2, n=5 and 6.21±1.24, n=6, in oocytes expressing rat cerebral cortex, α1β2 or α1β2γ2S human GABAA receptors respectively (values are given as means±s.e.mean), and the Hill coefficients were all close to unity. All this is consistent with the notion that pitrazepin acts as a competitive antagonist of these GABAA receptors; and that their antagonism by pitrazepin is not strongly dependent on the subunit composition of the receptors here studied.Since pitrazepin has been reported to act also at the benzodiazepine binding site, we studied the effect of the benzodiazepine antagonist Ro 15-1788 (flumazenil) on the inhibition of α1β2γ2S receptors by pitrazepin. Co-application of Ro 15-1788 did not alter the inhibiting effect of pitrazepin. Moreover, pitrazepin did not antagonize the potentiation of GABA-currents by flunitrazepam. All this suggests that pitrazepin does not affect the GABA receptor-chloride channel by interacting with the benzodiazepine receptor site. PMID:10369456

  4. [Vitamin K antagonist, direct oral anticoagulants: Where is the truth?

    PubMed

    Laroche, J-P; Schved, J-F

    2016-12-01

    Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) are now in competition. The companies are trying to replace VKA by DOACs, totally or at least greatly VKA should VKA disappear in favor of DOACs? There are still many questions about DOACs. The purpose of this article is to make a well-considered decision in this area. The aim is not to denigrate one or the other but to share things between these two families of anticoagulants. Physicians using these drugs must have a full knowledge about compared efficacy and safety. We feel necessary to increase distance between effective results of the clinical trials and industrial communication around DOACs.

  5. Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor

    PubMed Central

    Perrey, David A.; German, Nadezhda A.; Gilmour, Brian P.; Li, Jun-Xu; Harris, Danni L.; Thomas, Brian F.; Zhang, Yanan

    2013-01-01

    Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats. PMID:23941044

  6. Syntheses of 4,6'-epoxymorphinan derivatives and their pharmacologies.

    PubMed

    Nemoto, Toru; Fujii, Hideaki; Narita, Minoru; Miyoshi, Kan; Nakamura, Atsushi; Suzuki, Tsutomu; Nagase, Hiroshi

    2008-04-15

    A modification of the message site in the skeleton of naltrexone was carried out to improve the potency and selectivity of the compound for an opioid receptor subtype. In the course of conversion, we synthesized 7-membered ring ether derivatives, which had an inserted OCH(2) group between 4- and 6-positions of morphinan skeleton. One of the 7-membered ring ether derivatives possessed more potent antagonistic activity than naltrexone for the mu opioid receptor. Another compound possessing 17-methyl group derived from noroxycodone may be a mu opioid receptor partial agonist and showed analgesic activity. We are currently examining the subtype selectivity of these compounds.

  7. Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone.

    PubMed

    Lainscak, Mitja; Pelliccia, Francesco; Rosano, Giuseppe; Vitale, Cristiana; Schiariti, Michele; Greco, Cesare; Speziale, Giuseppe; Gaudio, Carlo

    2015-12-01

    Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more mineralocorticoid receptor-specific. From a marginal role as a potassium-sparing diuretic, spironolactone has been shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure. Also, spironolactone is safe and protective in arterial hypertension, particularly in patients with so-called resistant hypertension. Eplerenone is the second oral aldosterone antagonist available for the treatment of arterial hypertension and heart failure. Treatment with eplerenone has been associated with decreased blood pressure and improved survival for patients with heart failure and reduced left ventricular ejection fraction. Due to the selectivity of eplerenone for the aldosterone receptor, severe adverse effects such as gynecomastia and vaginal bleeding seem to be less likely in patients who take eplerenone than in those who take spironolactone. The most common and potentially dangerous side effect of spironolactone--hyperkalemia--is also observed with eplerenone but the findings from clinical trials do not indicate more hyperkalemia induced drug withdrawals. Treatment with eplerenone should be initiated at a dosage of 25mg once daily and titrated to a target dosage of 50mg once daily preferably within 4 weeks. Serum potassium levels and renal function should be assessed prior to initiating eplerenone therapy, and periodic monitoring is recommended, especially in patients at high risk of developing hyperkalemia.

  8. NMDA receptor antagonists extend the sensitive period for imprinting.

    PubMed

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

  9. Fires can benefit plants by disrupting antagonistic interactions.

    PubMed

    García, Y; Castellanos, M C; Pausas, J G

    2016-12-01

    Fire has a key role in the ecology and evolution of many ecosystems, yet its effects on plant-insect interactions are poorly understood. Because interacting species are likely to respond to fire differently, disruptions of the interactions are expected. We hypothesized that plants that regenerate after fire can benefit through the disruption of their antagonistic interactions. We expected stronger effects on interactions with specialist predators than with generalists. We studied two interactions between two Mediterranean plants (Ulex parviflorus, Asphodelus ramosus) and their specialist seed predators after large wildfires. In A. ramosus we also studied the generalist herbivores. We sampled the interactions in burned and adjacent unburned areas during 2 years by estimating seed predation, number of herbivores and fruit set. To assess the effect of the distance to unburned vegetation we sampled plots at two distance classes from the fire perimeter. Even 3 years after the fires, Ulex plants experienced lower seed damage by specialists in burned sites. The presence of herbivores on Asphodelus decreased in burned locations, and the variability in their presence was significantly related to fruit set. Generalist herbivores were unaffected. We show that plants can benefit from fire through the disruption of their antagonistic interactions with specialist seed predators for at least a few years. In environments with a long fire history, this effect might be one additional mechanism underlying the success of fire-adapted plants.

  10. A prototypical Sigma-1 receptor antagonist protects against brain ischemia.

    PubMed

    Schetz, John A; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W

    2007-11-21

    Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this study it potently protects against oxidative stress-related cell death in vitro at low concentrations. The protective potency of haloperidol and a number of other butyrophenone compounds positively correlate with their affinity for a cloned Sigma-1 receptor, and the protection is mimicked by a Sigma-1 receptor-selective antagonist (BD1063), but not an agonist (PRE-084). In vivo, an acute low dose (0.05 mg/kg s.c.) of haloperidol reduces by half the ischemic lesion volume induced by a transient middle cerebral artery occlusion. These in vitro and in vivo pre-clinical results suggest that a low dose of acutely administered haloperidol might have a novel application as a protective agent against ischemic cerebral stroke and other types of brain injury with an ischemic component.

  11. Abnormal reciprocal inhibition between antagonist muscles in Parkinson's disease.

    PubMed

    Meunier, S; Pol, S; Houeto, J L; Vidailhet, M

    2000-05-01

    Disynaptic Ia reciprocal inhibition acts, at the spinal level, by actively inhibiting antagonist motor neurons and reducing the inhibition of agonist motor neurons. The deactivation of this pathway in Parkinson's disease is still debated. Disynaptic reciprocal inhibition of H reflexes in the forearm flexor muscles was examined in 15 control subjects and 16 treated parkinsonian patients at rest and at the onset of a voluntary wrist flexion. Two patients were reassessed 18 h after withdrawal of antiparkinsonian medication. At rest, the level of Ia reciprocal inhibition between the wrist antagonist muscles was not significantly different between patients and controls. In contrast, clear abnormalities of this inhibition were revealed by voluntary movements in the patients. In normal subjects, at the onset of a wrist flexion, Ia reciprocal inhibition showed a large decrease, and we argue that this decrease is supraspinal in origin. On the less affected sides of the patients the descending modulation was still present but lower than in controls; on the more affected sides this modulation had vanished almost completely. These movement-induced abnormalities of disynaptic Ia reciprocal inhibition were closely associated with Parkinson's disease but were probably not dependent on L-dopa. They could play a role in the disturbances of precise voluntary movements observed in Parkinson's disease.

  12. CCR9 Antagonists in the Treatment of Ulcerative Colitis

    PubMed Central

    Bekker, Pirow; Ebsworth, Karen; Walters, Matthew J.; Berahovich, Robert D.; Ertl, Linda S.; Charvat, Trevor T.; Punna, Sreenivas; Powers, Jay P.; Campbell, James J.; Sullivan, Timothy J.; Jaen, Juan C.; Schall, Thomas J.

    2015-01-01

    While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a−/− mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a−/− mice. In the mdr1a−/− mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation. PMID:26457007

  13. The use of melanocortin antagonists in cachexia of chronic disease.

    PubMed

    Scarlett, Jarrad M; Marks, Daniel L

    2005-10-01

    Cachexia is a wasting syndrome that frequently develops in the setting of chronic diseases including cancer, congestive heart failure, chronic obstructive pulmonary disease, AIDS, renal failure and liver failure. Loss of lean body mass is believed to be a significant factor contributing to morbidity and mortality in these chronic diseases; however, there are currently no treatments available that have proven to be effective in reversing the progressive loss of lean body mass in cachectic patients. Evidence from animal models suggests a compelling link between inflammation, the central melanocortin system and cachexia. This review summarises the current evidence supporting the role of the melanocortin 4 (MC4) receptor subtype in cachexia, and discusses the development and use of small-molecule MC4 antagonists, which have proved to be effective in preventing the loss of lean body mass in animal models of cachexia. MC4 antagonists represent an attractive therapeutic approach for cachexia that may attenuate the loss of lean body mass in cachectic patients.

  14. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    SciTech Connect

    Yu, Hui; Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi; Wang, Zhanli; Liang, Huaping

    2010-11-05

    Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  15. Human homosexuality: a paradigmatic arena for sexually antagonistic selection?

    PubMed

    Camperio Ciani, Andrea; Battaglia, Umberto; Zanzotto, Giovanni

    2015-01-29

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait.

  16. Human Homosexuality: A Paradigmatic Arena for Sexually Antagonistic Selection?

    PubMed Central

    Ciani, Andrea Camperio; Battaglia, Umberto; Zanzotto, Giovanni

    2015-01-01

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. PMID:25635045

  17. Contrasting effects of intralocus sexual conflict on sexually antagonistic coevolution

    PubMed Central

    Pennell, Tanya M.; de Haas, Freek J. H.; Morrow, Edward H.; van Doorn, G. Sander

    2016-01-01

    Evolutionary conflict between the sexes can induce arms races in which males evolve traits that are detrimental to the fitness of their female partners, and vice versa. This interlocus sexual conflict (IRSC) has been proposed as a cause of perpetual intersexual antagonistic coevolution with wide-ranging evolutionary consequences. However, theory suggests that the scope for perpetual coevolution is limited, if traits involved in IRSC are subject to pleiotropic constraints. Here, we consider a biologically plausible form of pleiotropy that has hitherto been ignored in treatments of IRSC and arrive at drastically different conclusions. Our analysis is based on a quantitative genetic model of sexual conflict, in which genes controlling IRSC traits have side effects in the other sex, due to incompletely sex-limited gene expression. As a result, the genes are exposed to intralocus sexual conflict (IASC), a tug-of-war between opposing male- and female-specific selection pressures. We find that the interaction between the two forms of sexual conflict has contrasting effects on antagonistic coevolution: Pleiotropic constraints stabilize the dynamics of arms races if the mating traits are close to evolutionary equilibrium but can prevent populations from ever reaching such a state. Instead, the sexes are drawn into a continuous cycle of arms races, causing the buildup of IASC, alternated by phases of IASC resolution that trigger the next arms race. These results encourage an integrative perspective on the biology of sexual conflict and generally caution against relying exclusively on equilibrium stability analysis. PMID:26755609

  18. [Mineralocorticoid receptor antagonists and therapeutic strategies of cardiovascular damage].

    PubMed

    Verdugo, Fernando J; Montellano, Felipe A; Carreño, Juan E; Marusic, Elisa T

    2014-01-01

    In recent years, much attention has focused on the role of aldosterone and mineralocorticoid receptors (MRs) in the pathophysiology of hypertension and cardiovascular disease. Patients with primary aldosteronism, in whom angiotensin II levels are low, have a higher incidence of cardiovascular complications than patients with essential hypertension. The Randomized Aldactone Evaluation Study (RALES) demonstrated that adding a non-specific MR antagonist, spironolactone, to a standard therapy that included angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and digoxin, significantly reduced morbidity and mortality in patients with moderate to severe heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that the addition of a selective MR antagonist (ARM), eplerenone, to an optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These data suggest that aldosterone induces cardiac injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent cardiac injury, through mechanisms that cannot be simply explained by hemodynamic changes. Although, MRA are highly effective in patients with heart failure, the risk of hyperkalemia should not be overlooked. Serious hyperkalemia events were reported in some MRA clinical trials; however these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up.

  19. Is All Radiation-Induced Emesis Ameliorated by 5-HT3 Receptor Antagonists

    DTIC Science & Technology

    1992-01-01

    5 - HT3 receptor antagonists ;~// 9-72 Bernard M.I Rabin 0’) and Gregory L. Kingt2) -) Behavioral Sciences and 2 PhYSzo~o~y Dcpiarlrnvni . Arm,. ii - R...RY Exposing ferrets to gamuma rays or X-rays produces vomiting that can be attenuated by 5 - HT3 receptor antagonists and by subdiaphraqmatic vagotomy...Pretreating ferrets with serotonin type-3 ( 5 - HT3 ) receptor antagonists or performing bilateral subdiaphragmatic vagotomy reliably attenuates the

  20. Interaction of Pyridostigmine with the 5-HT(3) Receptor Antagonist Ondansetron in Guinea Pigs

    DTIC Science & Technology

    1993-05-13

    5 - HT3 RECEPTOR - ANTAGONIST .ONDANSETRON IN GUINEA PIGS BR. Capacio, CE. Byers...apart. REFERENCES 1. Fozard JR. 5 -HT; The Enigma Variations. =JE, 8, 501-506 (December 1987). 2. Watling KJ. 5 - HT3 Receptor Agonists and Antagonists . In... 5 -HT receptor subtype three antagonists (5HT 3 ) such as the compound ondansetron (OND) have been identified as useful in the treatment of

  1. In dermographic urticaria H2 receptor antagonists have a small but therapeutically irrelevant additional effect compared with H1 antagonists alone.

    PubMed

    Sharpe, G R; Shuster, S

    1993-11-01

    Two studies of the additional effect of an H2 receptor antagonist when given in combination with an H1 antagonist were undertaken in dermographic urticaria. Using a randomized, double-blind, crossover design in 19 patients, a combination of cetirizine (10 mg at night) and ranitidine (150 mg twice daily) was compared with a combination of cetirizine (10 mg at night) and placebo. The addition of ranitidine did not produce any significant difference in linear analogue scores for weal, itch or sleep disturbance. There was a significant depression of the frictional force/wealing response curve with an increase in wealing threshold (P < 0.0001) following the addition of H2 blockade. The wealing threshold was 54.7 +/- 4.4 (mean +/- SEM) g/mm2 for the H1 antagonist alone, and 73.2 +/- 5.7 for the combination of H1 and H2 antagonists. In a second similar study involving nine different patients, comparing terfenadine (120 mg twice daily) with a combination of terfenadine and ranitidine (150 mg twice daily), the weal threshold was 59.8 +/- 6.6 for the H1 antagonist alone, and 73.0 +/- 6.4 for the combination of H1 and H2 antagonists. Thus, in dermographic urticaria, adding an H2 antagonist to treatment with a potent H1 antagonist gives a small, significant reduction in wealing response, but no symptomatic benefit. We conclude that involvement of the H2 receptor in this urticarial disease is minimal, and does not justify the use of H2 receptor antagonists.

  2. Partial Agonist and Antagonist Activities of a Mutant Scorpion β-Toxin on Sodium Channels*

    PubMed Central

    Karbat, Izhar; Ilan, Nitza; Zhang, Joel Z.; Cohen, Lior; Kahn, Roy; Benveniste, Morris; Scheuer, Todd; Catterall, William A.; Gordon, Dalia; Gurevitz, Michael

    2010-01-01

    Scorpion β-toxin 4 from Centruroides suffusus suffusus (Css4) enhances the activation of voltage-gated sodium channels through a voltage sensor trapping mechanism by binding the activated state of the voltage sensor in domain II and stabilizing it in its activated conformation. Here we describe the antagonist and partial agonist properties of a mutant derivative of this toxin. Substitution of seven different amino acid residues for Glu15 in Css4 yielded toxin derivatives with both increased and decreased affinities for binding to neurotoxin receptor site 4 on sodium channels. Css4E15R is unique among this set of mutants in that it retained nearly normal binding affinity but lost its functional activity for modification of sodium channel gating in our standard electrophysiological assay for voltage sensor trapping. More detailed analysis of the functional effects of Css4E15R revealed weak voltage sensor trapping activity, which was very rapidly reversed upon repolarization and therefore was not observed in our standard assay of toxin effects. This partial agonist activity of Css4E15R is observed clearly in voltage sensor trapping assays with brief (5 ms) repolarization between the conditioning prepulse and the test pulse. The effects of Css4E15R are fit well by a three-step model of toxin action involving concentration-dependent toxin binding to its receptor site followed by depolarization-dependent activation of the voltage sensor and subsequent voltage sensor trapping. Because it is a partial agonist with much reduced efficacy for voltage sensor trapping, Css4E15R can antagonize the effects of wild-type Css4 on sodium channel activation and can prevent paralysis by Css4 when injected into mice. Our results define the first partial agonist and antagonist activities for scorpion toxins and open new avenues of research toward better understanding of the structure-function relationships for toxin action on sodium channel voltage sensors and toward potential toxin

  3. Partial agonist and antagonist activities of a mutant scorpion beta-toxin on sodium channels.

    PubMed

    Karbat, Izhar; Ilan, Nitza; Zhang, Joel Z; Cohen, Lior; Kahn, Roy; Benveniste, Morris; Scheuer, Todd; Catterall, William A; Gordon, Dalia; Gurevitz, Michael

    2010-10-01

    Scorpion β-toxin 4 from Centruroides suffusus suffusus (Css4) enhances the activation of voltage-gated sodium channels through a voltage sensor trapping mechanism by binding the activated state of the voltage sensor in domain II and stabilizing it in its activated conformation. Here we describe the antagonist and partial agonist properties of a mutant derivative of this toxin. Substitution of seven different amino acid residues for Glu(15) in Css4 yielded toxin derivatives with both increased and decreased affinities for binding to neurotoxin receptor site 4 on sodium channels. Css4(E15R) is unique among this set of mutants in that it retained nearly normal binding affinity but lost its functional activity for modification of sodium channel gating in our standard electrophysiological assay for voltage sensor trapping. More detailed analysis of the functional effects of Css4(E15R) revealed weak voltage sensor trapping activity, which was very rapidly reversed upon repolarization and therefore was not observed in our standard assay of toxin effects. This partial agonist activity of Css4(E15R) is observed clearly in voltage sensor trapping assays with brief (5 ms) repolarization between the conditioning prepulse and the test pulse. The effects of Css4(E15R) are fit well by a three-step model of toxin action involving concentration-dependent toxin binding to its receptor site followed by depolarization-dependent activation of the voltage sensor and subsequent voltage sensor trapping. Because it is a partial agonist with much reduced efficacy for voltage sensor trapping, Css4(E15R) can antagonize the effects of wild-type Css4 on sodium channel activation and can prevent paralysis by Css4 when injected into mice. Our results define the first partial agonist and antagonist activities for scorpion toxins and open new avenues of research toward better understanding of the structure-function relationships for toxin action on sodium channel voltage sensors and toward

  4. Spontaneous ECL cell carcinomas in cotton rats: natural course and prevention by a gastrin receptor antagonist.

    PubMed

    Martinsen, Tom C; Kawase, Shiro; Håkanson, Rolf; Torp, Sverre H; Fossmark, Reidar; Qvigstad, Gunnar; Sandvik, Arne K; Waldum, Helge L

    2003-12-01

    In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.

  5. Novel CC chemokine receptor 4 antagonist RS-1154 inhibits ovalbumin-induced ear swelling in mice.

    PubMed

    Nakagami, Yasuhiro; Kawashima, Kayo; Yonekubo, Kazuki; Etori, Maki; Jojima, Takaaki; Miyazaki, Shojiro; Sawamura, Ryoko; Hirahara, Kazuki; Nara, Futoshi; Yamashita, Makoto

    2009-12-10

    CC chemokine ligand 17 (CCL17/thymus and activation-regulated chemokine: TARC) and CCL22 (macrophage-derived chemokine: MDC) selectively bind to CC chemokine receptor 4 (CCR4). The CCR4 system is considered to be responsible for the pathology of allergic diseases such as atopic dermatitis. To find and develop potential medicines against allergic diseases, we screened an in-house library to search for compounds having a profile as a CCR4 antagonist. From among the screening hits, we focused on 3-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}quinazoline-2,4(1H,3H)-dione (named RS-1154), which had been newly synthesized in our laboratory. This compound inhibited the binding of [(125)I]CCL17 to human CCR4-expressing CHO cells with an IC(50) value of 27.7 nM and moreover inhibited CCL17-induced migration of DO11.10 mice-derived T helper 2 cells with an IC(50) value of 1.5 nM in vitro. We then examined the effect of RS-1154 in an ovalbumin-induced ear swelling assay. The ear thickness was decreased by intravenous administration of anti-CCL17 or anti-CCL22 antibodies, suggesting that the CCR4 system is involved in the ear swelling. Though partially, the oral administration of RS-1154 also significantly ameliorated the ear swelling at the doses of 30 and 100 mg/kg. Furthermore, the serum level of interleukin-4 decreased after the administration of RS-1154. In this study, we succeeded in obtaining a newly-synthesized compound, RS-1154, which has a potential to inhibit the chemotaxis of T helper 2 cells in vitro and to ameliorate ovalbumin-induced ear swelling in vivo. These results raise the possibility that RS-1154 or one of derivatives might become a therapeutic agent for atopic dermatitis patients.

  6. High antagonist potency of GT-2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models.

    PubMed

    Tedford, C E; Hoffmann, M; Seyedi, N; Maruyama, R; Levi, R; Yates, S L; Ali, S M; Phillips, J G

    1998-06-26

    GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and GT-2331 ((1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole) were developed as new potent histamine H3 receptor antagonists. The functional activity of these ligands on the histamine H3 receptor-mediated inhibition of neurogenic contraction of the guinea-pig jejunum and histamine H3 receptor-mediated inhibition of norepinephrine release from guinea-pig heart synaptosomes were investigated. GT-2227 and GT-2331 both antagonized the inhibitory effects of (R)-alpha-methylhistamine on the contraction induced by electrical field stimulation in the guinea-pig jejunum with pA2 values of 7.9+/-0.1 and 8.5+/-0.03, respectively. In addition, GT-2227 and GT-2331 antagonized the inhibition of norepinephrine release in cardiac synaptosomes by GT-2203 ((1R,2R)-trans-2-(1H-imidazol-4-yl)cyclopropylamine), a histamine H3 receptor agonist. The current results demonstrate the antagonist activity for both GT-2227 and GT-2331 in two functional assays for histamine H3 receptors.

  7. Binding of a Calcium Antagonist, [3H]Nitrendipine, to High Affinity Sites in Bovine Aortic Smooth Muscle and Canine Cardiac Membranes

    PubMed Central

    Williams, Lewis T.; Tremble, Patrice

    1982-01-01

    [3H]Nitrendipine, a potent calcium channel antagonist [3-ethyl-5-methyl-1-1,4-dihydro-2,6 - dimethyl - 4 - (3 - nitrophenyl) - 3,5 - pyridine carboxylate], was used to label high affinity binding sites on membranes prepared from bovine aortic smooth muscle. The binding of [3H]nitrendipine is rapid (t1/2 < 5 min) and reversible at 37°C. The binding sites have a high affinity for [3H]nitrendipine with an equilibrium dissociation constant of 2.1 nM. The density of sites is 40-60 fmol/mg of membrane protein. Analogues of nitrendipine compete for the binding sites with affinities consistent with their known biological effects as calcium antagonists. Nisoldipine, [isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine carboxylate], a calcium antagonist more potent than nifedipine [2,6-dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydropyridine] in relaxing vascular smooth muscle, has an affinity three-fold higher than that of nifedipine in competing for the binding sites. A biologically inactive derivative of nifedipine does not compete for [3H]nitrendipine binding. Verapamil (α-isopropyl-α[(N-methyl - N-homoveratryl) -α-aminopropyl]-3,4-dimethyoxyphenyl acetonitrile), a structurally different calcium antagonist, only partially (25%) inhibits binding at high concentrations (1 μM). Prazosin, an alpha adrenergic antagonist does not compete for [3H]nitrendipine binding sites. The binding of [3H]nitrendipine is not affected by 1.5 mM calcium. Canine cardiac membranes also have high affinity [3H]nitrendipine binding sites, (KD = 6 nM) but bovine erythrocytes do not. The relative affinities of nisoldipine and nifedipine for the cardiac membrane binding sites reflect the relative activities of these compounds as calcium channel antagonists. These results suggest that the [3H]nitrendipine binding sites are the sites through which dihydropyridines act as calcium channel antagonists. PMID:6282938

  8. Modulation of γ2-MSH hepatoprotection by antisense peptides and melanocortin subtype 3 and 4 receptor antagonists.

    PubMed

    Turcic, Petra; Stambuk, Nikola; Konjevoda, Pasko; Kelava, Tomislav; Gabricevic, Mario; Stojkovic, Ranko; Aralica, Gorana

    2015-01-01

    Melanocortins, i.e., melanocyte stimulating hormones (MSH) are peptides with strong antiinflammatory effects. The most investigated aspects of γ2-MSH are related to cardiovascular effects and natriuresis, with limited research available about its anti-inflammatory and cytoprotective effects. The aims of this study were: 1) to examine the effects of γ2-MSH and its derivative [D-Trp(8)]-γ2-MSH on the acetaminophen model of liver damage in CBA mice; 2) to evaluate the modulation of γ2-MSH hepatoprotection by melanocortin subtypes 3 and 4 receptor antagonists SHU 9119 and HS 024; 3) to define the importance of central MSH pharmacophore region (HFRW) by using antisense peptides LVKAT and VKAT. In this study, specific antagonists and antisense peptides were used to target central pharmacophore region of γ2-MSH and [D-Trp(8)]-γ2-MSH, enabling the evaluation of hepatoprotection from the standpoint of the receptor and pharmacophore blockade. The criteria for monitoring the effects of the hormones on the liver damage were alanine transaminase, aspartate transaminase activities (U/L), and pathohistological scoring of liver necrosis (scale 0-5). γ2-MSH (0.24 mg/kg) indicated hepatoprotective effects in comparison to control (p < 0.001). In contrast, [D-Trp(8)]-γ2-MSH did not show any hepatoprotective effects. Application of antagonists SHU 9119 and HS 024, and antisense peptides LVKAT and VKAT, also did not show any hepatoprotective effects. In fact, when combined with γ2-MSH, it annulled its hepatoprotective effect. The results provide evidence for hepatoprotective and antiinflammatory effects of the γ2-MSH in the liver.

  9. Potent inhibition of alcohol self-administration in alcohol-preferring rats by a κ-opioid receptor antagonist.

    PubMed

    Cashman, John R; Azar, Marc R

    2014-07-01

    A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.

  10. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

    PubMed Central

    Iadarola, Nicolas D.; Niciu, Mark J.; Richards, Erica M.; Vande Voort, Jennifer L.; Ballard, Elizabeth D.; Lundin, Nancy B.; Nugent, Allison C.; Machado-Vieira, Rodrigo

    2015-01-01

    Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and

  11. 6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode.

    PubMed

    Ulven, Trond; Frimurer, Thomas M; Receveur, Jean-Marie; Little, Paul Brian; Rist, Oystein; Nørregaard, Pia K; Högberg, Thomas

    2005-09-08

    Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.

  12. 2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.

    PubMed

    Slee, Deborah H; Moorjani, Manisha; Zhang, Xiaohu; Lin, Emily; Lanier, Marion C; Chen, Yongsheng; Rueter, Jaimie K; Lechner, Sandra M; Markison, Stacy; Malany, Siobhan; Joswig, Tanya; Santos, Mark; Gross, Raymond S; Williams, John P; Castro-Palomino, Julio C; Crespo, María I; Prat, Maria; Gual, Silvia; Díaz, José-Luis; Jalali, Kayvon; Sai, Yang; Zuo, Zhiyang; Yang, Chun; Wen, Jenny; O'Brien, Zhihong; Petroski, Robert; Saunders, John

    2008-03-27

    Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

  13. Tamoxifen resistant breast cancer: coregulators determine the direction of transcription by antagonist-occupied steroid receptors.

    PubMed

    Takimoto, G S; Graham, J D; Jackson, T A; Tung, L; Powell, R L; Horwitz, L D; Horwitz, K B

    1999-01-01

    Pharmacological antagonists of steroid receptor action had been thought to exert their effects by a passive mechanism driven principally by the ability of the antagonist to compete with agonist for the ligand binding site. However, recent analyses of antagonist-occupied receptor function suggest a more complex picture. Antagonists can be subdivided into two groups, type I, or pure antagonists, and type II, or mixed antagonists that can have variable transcriptional activity based upon differential dimerization and DNA binding properties. This led us to propose that receptor antagonism may not simply be a passive competition for the ligand binding site, but may, in some cases, involve active recruitment of corepressor or coactivator proteins to produce a mixed transcriptional phenotype. We used a yeast two-hybrid screen to identify proteins that interact specifically with antagonist-occupied receptors. Two proteins have been characterized: L7/SPA, a ribosome-associated protein that is localized in both the cytoplasm and nucleus, but with no known extranucleolar nuclear function; and hN-CoR, the human homolog of the mouse thyroid receptor corepressor mN-CoR. In in vivo transcription assays we show that L7/SPA enhances the partial agonist activity of type II mixed antagonists, and that N-CoR and the related corepressor, SMRT, suppresses it. The coregulators do not affect agonists or pure antagonists. Moreover, the net agonist activity seen with mixed antagonists is a function of the ratio of coactivator to corepressor. Based upon these results, we proposed that in breast tumors the inappropriate agonist activity seen with therapeutic antagonists such as tamoxifen is responsible for the hormone-resistant state. To confirm this, we are quantitating coactivator/corepressor ratios in breast tumor cells lines and clinical breast cancers. Results should provide new insights into the mechanisms underlying the progression of breast cancer to hormone resistance, and may

  14. Cangrelor: a novel P2Y12 receptor antagonist.

    PubMed

    Norgard, Nicholas B

    2009-08-01

    Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Current antiplatelet agents (aspirin, clopidogrel and glycoprotein IIb/IIIa antagonists) have demonstrated the capacity to reduce major adverse cardiac events. However, these agents have limitations that compromise their clinical utility. The platelet P2Y12 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies. Cangrelor is a potent, competitive inhibitor of the P2Y12 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP-induced platelet aggregation. This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis.

  15. 1/f scaling in heart rate requires antagonistic autonomic control

    NASA Astrophysics Data System (ADS)

    Struzik, Zbigniew R.; Hayano, Junichiro; Sakata, Seiichiro; Kwak, Shin; Yamamoto, Yoshiharu

    2004-11-01

    We present systematic evidence for the origins of 1/f -type temporal scaling in human heart rate. The heart rate is regulated by the activity of two branches of the autonomic nervous system: the parasympathetic (PNS) and the sympathetic (SNS) nervous systems. We examine alterations in the scaling property when the balance between PNS and SNS activity is modified, and find that the relative PNS suppression by congestive heart failure results in a substantial increase in the Hurst exponent H towards random-walk scaling 1/f2 and a similar breakdown is observed with relative SNS suppression by primary autonomic failure. These results suggest that 1/f scaling in heart rate requires the intricate balance between the antagonistic activity of PNS and SNS.

  16. Vasopressin receptor antagonists, heart failure, and polycystic kidney disease.

    PubMed

    Torres, Vicente E

    2015-01-01

    The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.

  17. Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists.

    PubMed

    Ganesh, Thota; Jiang, Jianxiong; Shashidharamurthy, Rangaiah; Dingledine, Ray

    2013-07-11

    Prostanoid receptor EP2 is emerging as a novel target for development of anti-inflammatory drugs for the treatment of chronic neurodegenerative and peripheral diseases; however, the availability of EP2 antagonist probes for exploration of peripheral disease models is very limited. We now report identification and characterization of a novel chemical class of compounds that show nanomolar potency and competitive antagonism of the EP2 receptor. A compound in this class, TG6-129, showed prolonged plasma half-life and did not cross the blood brain barrier. This compound also suppressed the induction of inflammatory mRNA markers in a macrophage cell line upon activation of EP2. Thus, this compound could be useful as a probe for a variety of peripheral chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease, in which EP2 appears to play a pathogenic role.

  18. PAI-1 antagonists: the promise and the peril.

    PubMed

    Vaughan, Douglas E

    2011-01-01

    The plasminogen activator (i.e., fibrinolytic) system is one of the key endogenous defense mechanisms against intravascular thrombosis. Thrombolytic agents represent the only direct way of augmenting fibrinolytic activity in humans, and have proven to be of value in the treatment of acute myocardial infarction and stroke. Although these agents are efficacious in the acute setting, they are not a viable option for long-term use. Net fibrinolytic activity is plasma is largely determined by the balance between tissue-type plasminogen activator (t-PA) and its natural, fast-acting inhibitor, plasminogen activator inhibitor-1 (PAI-1). The recent development of specific PAI-1 antagonists promises to expand the limits of understanding of the role of the fibrinolytic system in human disease, and to break through the current confines of therapeutic options that can effectively restore and augment the activity of the fibrinolytic system.

  19. Nef proteins from simian immunodeficiency viruses are tetherin antagonists

    PubMed Central

    Zhang, Fengwen; Wilson, Sam J.; Langford, Wilmina; Virgen, Beatriz; Gregory, Devon; Johnson, Marc; Munch, Jan; Kirchhoff, Frank; Bieniasz, Paul D.; Hatziioannou, Theodora

    2010-01-01

    The tetherin/BST2/CD317 protein blocks the release of HIV-1 and other enveloped viruses by inducing tethering of nascent particles to infected cell surfaces. The HIV-1 Vpu protein antagonizes the antiviral activity of human but not monkey tetherins and many simian immunodeficiency viruses (SIVs) do not encode Vpu. Here, we show that the apparently ‘missing’ anti-tetherin activity in SIVs has been acquired by several SIV Nef proteins. Specifically, SIVMAC/SIVSMM, SIVAGM and SIVBLU Nef proteins can suppress tetherin activity. Notably, tetherin antagonism by SIV Nef proteins is species-specific, is genetically separable from other Nef activities and is most evident with simian rather than human tetherin proteins. Accordingly, a critical determinant of sensitivity to SIVMAC Nef in the tetherin cytoplasmic tail is variable in nonhuman primate tetherins and deleted in human tetherin, likely due to selective pressures imposed by viral antagonists, perhaps including Nef proteins. PMID:19501037

  20. M sub 1 muscarinic antagonists interact with. sigma. recognition sites

    SciTech Connect

    Hudkins, R.L. ); DeHaven-Hudkins, D.L. )

    1991-01-01

    The M{sub 1}-selective muscarinic antagonists aprophen, caramiphen, carbetapentane, 2-DAEX, dicyclomine, hexahydrosiladifenidol, iodocaramiphen, nitrocaramiphen, oxybutynin and trihexyphenidyl potently inhibited binding to {sigma} sites in brain. Both basic ester and non-ester structural type compounds which exhibit affinity for the muscarinic receptor also demonstrated affinity for the {sigma} site, while the classical antimuscarinic agents atropine and QNB, and the tricyclic pirenzepine, were ineffective in binding to this site. The authors also observed a significant correlation between the K{sub i} values for {sigma}compounds to inhibit ({sup 3}H)pirenzepine binding and their IC{sub 50} values to inhibit carbachol-stimulated phosphoinositide turnover. These observations may aid in elucidating the relationship of {sigma} binding to inhibition of phosphoinositide turnover stimulated by cholinergic agonists.

  1. Physico-chemical pathways in radioprotective action of calmodulin antagonists

    NASA Astrophysics Data System (ADS)

    Varshney, Rajeev; Kale, R. K.

    1996-04-01

    Ghost membranes prepared from erythrocytes of Swiss albino mice were irradiated with gamma rays at a dose rate of 0.9 Gy/s. The fluidity of membrane decreased with radiation dose and in the presence of calmodulin antagonists (CA) like chlorpromazine (CPZ), promethazine (PMZ) and trimeprazine (TMZ) it increased. Radiation induced release of Ca 2+ from membranes. This release was inhibited by CA mainly by CPZ and PMZ. Being Ca 2+ dependent, the changes in the activity of acetylcholine estrase (AchE) following irradiation was also studied. Radiation decreased the activity of AchE in dose dependent manner. Presence of CPZ and PMZ diminished the radiation induced inhibition of AchE but not in the presence of TMZ at the lower concentration tested. It is suggested that apart from scavenging of free radicals, CA perhaps exert their euxoic radioprotective effect through Ca 2+ dependent processes.

  2. Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

    PubMed Central

    2014-01-01

    We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl LewisX was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole–dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity. PMID:25221666

  3. Mesenteric vascular reactivity to histamine receptor agonists and antagonists. [Dogs

    SciTech Connect

    Walus, K.M.; Fondacaro, J.D.; Jacobson, E.D.

    1981-05-01

    Response patterns of intestinal blood flow, oxygen extraction and consumption, blood flow distribution, and motility were assessed during intraarterial infusions of histamine, histamine after H1 or H2 blockade, dimaprit or dimaprit after H2 blockade. Histamine produced an initial peak response of blood flow with a slow decrease thereafter. Oxygen extraction was evenly depressed throughout the infusion, and oxygen consumption increased at the beginning. All initial responses were blocked by tripelennamine. Ranitidine, a new H2 antagonist, accelerated the decay of all responses. Dimaprit produced effects identical to those of histamine after tripelennamine. Distribution of blood flow was unchanged at the beginning of histamine infusion, but subsequently showed a shift to muscularis which was blocked by tripelennamine. Histamine usually stimulated intestinal contractions and this effect was abolished by tripelennamine. Thus, H1 stimulation, besides producing an initial vasodilation, increases oxygen uptake and redistributes flow to the muscularis.

  4. Identification of Bexarotene as a PPARγ Antagonist with HDX

    PubMed Central

    Marciano, David P.; Kuruvilla, Dana S.; Pascal, Bruce D.; Griffin, Patrick R.

    2015-01-01

    The retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ), to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX) mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions. PMID:26451138

  5. Oxycodone with an opioid receptor antagonist: A review.

    PubMed

    Davis, Mellar P; Goforth, Harold W

    2016-01-01

    The rationale for putting opioid antagonists with an agonist is to improve pain control, to reduce side effects, and/or to reduce abuse. The combination of prolonged release (PR) oxycodone and naloxone reduces constipation as demonstrated in multiple studies and has been designated a tamper-resistant opioid by the Food and Drug Administration. Bioequivalence of the combination product compared with PR oxycodone has not been established. Several of the pivotal studies provided suboptimal laxative support in the control arm of the randomized trials. Two noninferiority trials have demonstrated equivalent analgesia between PR oxycodone and the combination product at doses of less than 120 mg of oxycodone per day. There appears to be an analgesic ceiling above 80-120 mg of oxycodone per day. Safety monitoring during randomized trials was not been well described in published manuscripts. Benefits appear to be better for those with chronic noncancer pain compared with individuals with cancer when constipation was the primary outcome.

  6. Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors.

    PubMed

    Fride, Ester; Ponde, Datta; Breuer, Aviva; Hanus, Lumir

    2005-06-01

    Delta-9 tetrahydrocannabinol (Delta(9)-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Delta(9)-THC activates cannabinoid CB(1) and CB(2) receptors and induces psychoactive and peripheral effects. (-)-CBD possesses no, or very weak affinity for these receptors. We tested a series of (+)- and (-)-CBD derivatives for central and peripheral effects in mice. None of the (-)-CBD derivatives were centrally active, yet most inhibited intestinal motility. Of the five (+)-CBD derivatives, all with CB(1) receptor affinity, only (+)-7-OH-CBD-DMH (DMH=1,1-dimethylheptyl), acted centrally, while all five arrested defecation. The effects of (+)-CBD-DMH and (+)-7-OH-CBD-DMH were inhibited by the CB(1) receptor antagonist SR141716. The CB(2) receptor antagonist SR144528, and the vanilloid TRPV1 receptor antagonist capsazepine, had no influence. Further, the (-)-CBD derivatives (-)-7-COOH-CBD and (-)-7-COOH-CBD-DMH, displayed antiinflammatory activity. We suggest that (+)-CBD analogues have mixed agonist/antagonist activity in the brain. Second, (-)-CBD analogues which are devoid of cannabinoid receptor affinity but which inhibit intestinal motility, suggest the existence of a non-CB(1), non-CB(2) receptor. Therefore, such analogues should be further developed as antidiarrheal and/or antiinflammatory drugs. We propose to study the therapeutic potential of (-)- and (+)-CBD derivatives for complex conditions such as inflammatory bowel disease and cystic fibrosis.

  7. Antagonistic pleiotropy involving promoter sequences in a virus

    PubMed Central

    Presloid, John B.; Ebendick-Corpus, Bonnie E.; Zárate, Selene; Novella, Isabel S.

    2008-01-01

    Selection of specialist genotypes, that is, populations with limited niche width, promotes the maintenance of diversity. Specialization to a particular environment may have a cost in other environments, including fitness tradeoffs. When the tradeoffs are the result of mutations that have a beneficial effect in the selective environment, but a deleterious effect in other environment, we have antagonistic pleiotropy. Alternatively, tradeoffs can result from the fixation of mutations that are neutral in the selective environment but have a negative effect in other environment, and thus the tradeoff is due to mutation accumulation. We tested the mechanisms underlying the fitness tradeoffs observed during adaptation to persistent infection of vesicular stomatitis virus in insect cells by sequencing the full-length genomes of twelve strains with a history of replication in a single niche (acute mammalian infection or persistent insect infection) or in temporally-heterogeneous niches, and correlated genetic and fitness changes. Ecological theory predicts a correlation between the selective environment and the niche width of the evolved populations, such that adaptation to single niches should lead to the selection of specialists and niche cycling should result in the selection of generalists. Contrary to this expectation, adaptation to one of the single niches resulted in a generalist and adaptation to a heterogeneous environment led to the selection of a specialist. Only one-third of the mutations that accumulated during persistent infection had a fitness cost that could be explained in all cases by antagonistic pleiotropy. Mutations involved in fitness tradeoffs included changes in regulatory sequences, particularly at the 3′ termini of the genomes, which contain the single promoter that controls viral transcription and replication. PMID:18644381

  8. SP 01-3 ALDOSTERONE ANTAGONISTS IN HEART FAILURE.

    PubMed

    Johnston, Colin

    2016-09-01

    Aldosterone's deleterious pathophysiological effects on the cardiovascular system if blocked by mineralcorticord antagonists (MRAs) logically should lead to improvement in heart function and outcomes in heart failure (HF). The first trial to test this hypothesis was tthe RALES trial in 1999 which treated patients with class III-IV HF with spironolactone. It showed significant reduction in mortality and cardiovascular hospitalzation rates. This was confirmed & extended in EMHASIS-HF RCT with classs II-III being treated with ACEIs & BB who received placebo or elperinone (a MRA) with again a statistically significant fall in mortality & hospitalization.The possible cardioprotective effects of MRA post acute myocardial infarct (MI) is less clear. The EPHESUS RCT in 2003 demostrated that elperinone given 3-14 days AMI in patients with early signs of HF reduced mortality & morbidity. However in the ALBTROSS trial using spironolactone 2 days after AMI showed no benfit in patients without HF but in a subgroup with ST elevation there was a 80% reduction in mortality after 6 months. However a recent meta-analysis from 25 RCT with data invovling 19,333 patients with either HF or post MI assigned aldosterone antagonists (AA)or placebo showed a 18% reduction in mortality including a 20% fall in CV mortality and a 19% reduction in SCD.The role of AA in HFPEF is even even more contraversial. The TOPCAT RCT of 3445 patients with symptomatc HFPEF randomised to spironolactone failed to meet the primary composite end point of death, aborted cardiac arrest or hospitalization although there was a reduction in hospitalization for HF (HR 0.83 P = 0.04).The differences between selective or non-selective MRAs, their ADRs & off target effects will also be discussed.

  9. Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

    PubMed

    Casey, Darren P; Madery, Brandon D; Pike, Tasha L; Eisenach, John H; Dietz, Niki M; Joyner, Michael J; Wilkins, Brad W

    2009-10-01

    We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

  10. Guanidinoethyl sulphonate is a glycine receptor antagonist in striatum.

    PubMed

    Sergeeva, Olga A; Chepkova, Aisa N; Haas, Helmut L

    2002-11-01

    1. Guanidinoethyl sulphonate (GES) is an analogue of taurine and an inhibitor of taurine transport. Interactions of GES with GABA(A) and glycine receptors are studied by whole cell recording and fast drug application in isolated striatal neurons of the mouse. 2. We confirm that GES is a weak agonist at GABA(A) receptors, and is able to antagonize GABA-evoked responses. GES did not gate GlyR. 3. GES antagonized glycine responses in a concentration-dependent and surmountable manner. Glycine dose-response curves were shifted to the right by GES (0.5 mM), yielding EC(50)s and Hill coefficients of 62 micro M and 2.5 in control, 154 micro M and 1.3 in the presence of GES. 4. GlyR-mediated taurine responses were competitively antagonized by GES. Taurine dose-response curves, in contrast to the glycine dose-response curves were shifted by GES to the right in a parallel manner. 5. The GlyR-block by GES was not voltage-dependent. 6. In contrast to our findings in the mouse, in rat striatal neurons which lack expression of the alpha3 GlyR subunit, GES shifted the glycine dose-response curve to the right in a parallel way without affecting the maximal response. Subtype-specificity of the GES action at GlyR must await further investigation in artificial expression systems. 7. We conclude that GES is a competitive antagonist at GlyR. The antagonistic action of GES at inhibitory ionotropic receptors can explain its epileptogenic action. Care must be taken with the interpretation of data on GES evoked taurine release.

  11. Sexually antagonistic cytonuclear fitness interactions in Drosophila melanogaster.

    PubMed Central

    Rand, D M; Clark, A G; Kann, L M

    2001-01-01

    Theoretical and empirical studies have shown that selection cannot maintain a joint nuclear-cytoplasmic polymorphism within a population except under restrictive conditions of frequency-dependent or sex-specific selection. These conclusions are based on fitness interactions between a diploid autosomal locus and a haploid cytoplasmic locus. We develop a model of joint transmission of X chromosomes and cytoplasms and through simulation show that nuclear-cytoplasmic polymorphisms can be maintained by selection on X-cytoplasm interactions. We test aspects of the model with a "diallel" experiment analyzing fitness interactions between pairwise combinations of X chromosomes and cytoplasms from wild strains of Drosophila melanogaster. Contrary to earlier autosomal studies, significant fitness interactions between X chromosomes and cytoplasms are detected among strains from within populations. The experiment further demonstrates significant sex-by-genotype interactions for mtDNA haplotype, cytoplasms, and X chromosomes. These interactions are sexually antagonistic--i.e., the "good" cytoplasms in females are "bad" in males--analogous to crossing reaction norms. The presence or absence of Wolbachia did not alter the significance of the fitness effects involving X chromosomes and cytoplasms but tended to reduce the significance of mtDNA fitness effects. The negative fitness correlations between the sexes demonstrated in our empirical study are consistent with the conditions that maintain cytoplasmic polymorphism in simulations. Our results suggest that fitness interactions with the sex chromosomes may account for some proportion of cytoplasmic variation in natural populations. Sexually antagonistic selection or reciprocally matched fitness effects of nuclear-cytoplasmic genotypes may be important components of cytonuclear fitness variation and have implications for mitochondrial disease phenotypes that differ between the sexes. PMID:11560895

  12. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra).

    PubMed

    Simons, Rudy; Vincken, Jean-Paul; Mol, Loes A M; The, Susan A M; Bovee, Toine F H; Luijendijk, Teus J C; Verbruggen, Marian A; Gruppen, Harry

    2011-07-01

    The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ERα and ERβ). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ERα. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ERα or ERβ subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ERα-selective antagonism, similar to the ERα-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6 × 10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ERα.

  13. Discovery of a potent and selective α3β4 nicotinic acetylcholine receptor antagonist from an α-conotoxin synthetic combinatorial library.

    PubMed

    Chang, Yi-Pin; Banerjee, Jayati; Dowell, Cheryl; Wu, Jinhua; Gyanda, Reena; Houghten, Richard A; Toll, Lawrence; McIntosh, J Michael; Armishaw, Christopher J

    2014-04-24

    α-Conotoxins are disulfide-rich peptide neurotoxins that selectively inhibit neuronal nicotinic acetylcholine receptors (nAChRs). The α3β4 nAChR subtype has been identified as a novel target for managing nicotine addiction. Using a mixture-based positional-scanning synthetic combinatorial library (PS-SCL) with the α4/4-conotoxin BuIA framework, we discovered a highly potent and selective α3β4 nAChR antagonist. The initial PS-SCL consisted of a total of 113 379 904 sequences that were screened for α3β4 nAChR inhibition, which facilitated the design and synthesis of a second generation library of 64 individual α-conotoxin derivatives. Eleven analogues were identified as α3β4 nAChR antagonists, with TP-2212-59 exhibiting the most potent antagonistic activity and selectivity over the α3β2 and α4β2 nAChR subtypes. Final electrophysiological characterization demonstrated that TP-2212-59 inhibited acetylcholine evoked currents in α3β4 nAChRs heterogeneously expressed in Xenopus laevis oocytes with a calculated IC50 of 2.3 nM and exhibited more than 1000-fold selectivity over the α3β2 and α7 nAChR subtypes. As such, TP-2212-59 is among the most potent α3β4 nAChRs antagonists identified to date and further demonstrates the utility of mixture-based combinatorial libraries in the discovery of novel α-conotoxin derivatives with refined pharmacological activity.

  14. Peripheral 5-HT2-like receptors. Can they be classified with the available antagonists?

    PubMed Central

    Leff, P.; Martin, G. R.

    1986-01-01

    Interactions between 5-hydroxytryptamine (5-HT) and the so-called 5-HT2 receptor antagonists ketanserin, spiperone, trazodone and methysergide were studied in isolated preparations of the rabbit aorta, rat jugular vein, and rat caudal artery. Trazodone and spiperone were apparently simple competitive antagonists since they produced antagonism that was surmountable over the concentration range studied and, in each tissue, their apparent affinity appeared to be independent of the antagonist concentration. Furthermore, concentration-ratios obtained with the two antagonists in combination suggested that antagonism was additive, implying mutual competition with a single population of 5-HT receptors. Ketanserin was a non-surmountable antagonist of 5-HT in the rat caudal artery and methysergide demonstrated surmountable, competitive antagonism only in the rabbit aorta. Antagonist dissociation constants estimated for apparently competitive interactions showed that ketanserin, spiperone and trazodone expressed affinities which differed according to the tissue used. In the case of trazodone, affinity estimates differed by as much as 12 fold. These discrepancies were independent of the 5-HT receptor agonist used and could not be attributed to an inadequate equilibration of the antagonist. These results can be interpreted in two ways: either the receptors in the different tissues are heterogeneous or the antagonists used here must be considered as unreliable probes for the classification of 5-HT2-like receptors. PMID:2943354

  15. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    PubMed Central

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today. PMID:27882209

  16. Histamine-Induced Hypotension Modified by H1 and H2 Antagonists.

    DTIC Science & Technology

    The hypotensive response of monkeys to exogenous histamine was measured when the histamine was given without antagonist, after chlorpheniramine (10...percent maximal response was: without antagonist, 0.115 micrograms/kg; after chlorpheniramine , 13.5 micrograms/kg; after chlorpheniramine and

  17. A long-acting GH receptor antagonist through fusion to GH binding protein

    PubMed Central

    Wilkinson, Ian R.; Pradhananga, Sarbendra L.; Speak, Rowena; Artymiuk, Peter J.; Sayers, Jon R.; Ross, Richard J.

    2016-01-01

    Acromegaly is a human disease of growth hormone (GH) excess with considerable morbidity and increased mortality. Somatostatin analogues are first line medical treatment but the disease remains uncontrolled in up to 40% of patients. GH receptor (GHR) antagonist therapy is more effective but requires frequent high-dose injections. We have developed an alternative technology for generating a long acting potent GHR antagonist through translational fusion of a mutated GH linked to GH binding protein and tested three candidate molecules. All molecules had the amino acid change (G120R), creating a competitive GHR antagonist and we tested the hypothesis that an amino acid change in the GH binding domain (W104A) would increase biological activity. All were antagonists in bioassays. In rats all antagonists had terminal half-lives >20 hours. After subcutaneous administration in rabbits one variant displayed a terminal half-life of 40.5 hours. A single subcutaneous injection of the same variant in rabbits resulted in a 14% fall in IGF-I over 7 days. In conclusion: we provide proof of concept that a fusion of GHR antagonist to its binding protein generates a long acting GHR antagonist and we confirmed that introducing the W104A amino acid change in the GH binding domain enhances antagonist activity. PMID:27731358

  18. Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.

    PubMed

    Kaizerman, Jacob A; Aaron, Wade; An, Songzhu; Austin, Richard; Brown, Matt; Chong, Angela; Huang, Tom; Hungate, Randall; Jiang, Ben; Johnson, Michael G; Lee, Gary; Lucas, Brian S; Orf, Jessica; Rong, Minqing; Toteva, Maria M; Wickramasinghe, Dineli; Xu, Guifen; Ye, Qiuping; Zhong, Wendy; McMinn, Dustin L

    2010-08-01

    Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.

  19. Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists.

    PubMed

    Kangas, Brian D; Delatte, Marcus S; Vemuri, V Kiran; Thakur, Ganesh A; Nikas, Spyridon P; Subramanian, Kumara V; Shukla, Vidyanand G; Makriyannis, Alexandros; Bergman, Jack

    2013-03-01

    Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors.

  20. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    PubMed

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  1. Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors.

    PubMed

    Wu, Chien-Huang; Wang, Chuan-Jen; Chang, Chun-Ping; Cheng, Yung-Chi; Song, Jen-Shin; Jan, Jiing-Jyh; Chou, Ming-Chen; Ke, Yi-Yu; Ma, Jing; Wong, Ying-Chieh; Hsieh, Tsung-Chih; Tien, Yun-Chen; Gullen, Elizabeth A; Lo, Chen-Fu; Cheng, Chia-Yi; Liu, Yu-Wei; Sadani, Amit A; Tsai, Chia-Hua; Hsieh, Hsin-Pang; Tsou, Lun K; Shia, Kak-Shan

    2015-02-12

    Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4(+)/CD34(+) stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.

  2. Design and synthesis of a metabolically stable and potent antitussive agent, a novel delta opioid receptor antagonist, TRK-851.

    PubMed

    Sakami, Satoshi; Kawai, Koji; Maeda, Masayuki; Aoki, Takumi; Fujii, Hideaki; Ohno, Hiroshi; Ito, Tsuyoshi; Saitoh, Akiyoshi; Nakao, Kaoru; Izumimoto, Naoki; Matsuura, Hirotoshi; Endo, Takashi; Ueno, Shinya; Natsume, Kazuto; Nagase, Hiroshi

    2008-09-01

    We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).

  3. The influence of the long chain fatty acid on the antagonistic activities of Rhizobium sin-1 lipid A

    PubMed Central

    Zhang, Yanghui; Wolfert, Margreet A.; Boons, Geert-Jan

    2007-01-01

    The lipid A from nitrogen-fixing bacterial species R. sin-1 is structurally unusual due to lack of phosphates and the presence of a 2-aminogluconolactone and a very long chain fatty acid, 27-hydroxyoctacosanoic acid (27OHC28:0), moiety. This structurally unusual lipid A can antagonize TNF-α production by human monocytes induced by E. coli LPS. To establish the relevance of the unusual long chain 27-hydroxyoctacosanoic acid for antagonistic properties, a highly convergent strategy for the synthesis of several derivatives of the lipid A of Rhizobium sin-1 has been developed. Compound 1 is a natural R. sin-1 lipid A having a 27-hydroxyoctacosanoic acid at C-2′, compound 2 contains an octacosanoic acid moiety at this position, and compound 3 is modified by a short chain tetradecanoic acid. Cellular activation studies with a human monocytic cell line have shown that the octacosanoic acid is important for optimal antagonistic properties. The hydroxyl of the natural 27-hydroxyoctacosanoic moiety does, however, not account for inhibitory activity. The resulting structure activity relationships are important for the design of compounds for the treatment of septic shock. PMID:17513113

  4. Antibiotic discovery throughout the Small World Initiative: A molecular strategy to identify biosynthetic gene clusters involved in antagonistic activity.

    PubMed

    Davis, Elizabeth; Sloan, Tyler; Aurelius, Krista; Barbour, Angela; Bodey, Elijah; Clark, Brigette; Dennis, Celeste; Drown, Rachel; Fleming, Megan; Humbert, Allison; Glasgo, Elizabeth; Kerns, Trent; Lingro, Kelly; McMillin, MacKenzie; Meyer, Aaron; Pope, Breanna; Stalevicz, April; Steffen, Brittney; Steindl, Austin; Williams, Carolyn; Wimberley, Carmen; Zenas, Robert; Butela, Kristen; Wildschutte, Hans

    2017-01-22

    The emergence of bacterial pathogens resistant to all known antibiotics is a global health crisis. Adding to this problem is that major pharmaceutical companies have shifted away from antibiotic discovery due to low profitability. As a result, the pipeline of new antibiotics is essentially dry and many bacteria now resist the effects of most commonly used drugs. To address this global health concern, citizen science through the Small World Initiative (SWI) was formed in 2012. As part of SWI, students isolate bacteria from their local environments, characterize the strains, and assay for antibiotic production. During the 2015 fall semester at Bowling Green State University, students isolated 77 soil-derived bacteria and genetically characterized strains using the 16S rRNA gene, identified strains exhibiting antagonistic activity, and performed an expanded SWI workflow using transposon mutagenesis to identify a biosynthetic gene cluster involved in toxigenic compound production. We identified one mutant with loss of antagonistic activity and through subsequent whole-genome sequencing and linker-mediated PCR identified a 24.9 kb biosynthetic gene locus likely involved in inhibitory activity in that mutant. Further assessment against human pathogens demonstrated the inhibition of Bacillus cereus, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus in the presence of this compound, thus supporting our molecular strategy as an effective research pipeline for SWI antibiotic discovery and genetic characterization.

  5. Tailoring mineralocorticoid receptor antagonist therapy in heart failure patients: are we moving towards a personalized approach?

    PubMed

    Ferreira, João Pedro; Mentz, Robert J; Pizard, Anne; Pitt, Bertram; Zannad, Faiez

    2017-04-12

    The aim of personalized medicine is to offer a tailored approach to each patient in order to provide the most effective therapy, while reducing risks and side effects. The use of mineralocorticoid receptor antagonists (MRAs) has demonstrated major benefits in heart failure with reduced ejection fraction (HFrEF), results with challenging inconsistencies in heart failure with preserved ejection fraction (HFpEF), and 'neutral' preliminary results in acute heart failure. Data derived from landmark trials are generally applied in a 'one size fits all' manner and the development and implementation of more personalized MRA management would offer the potential to improve outcomes and reduce side effects. However, the personalization of pharmacotherapy regimens remains poorly defined in the cardiovascular field (in light of current knowledge) and until further trials targeting specific subpopulations have been conducted, MRAs should be provided to the great majority of HFrEF patients in the absence of contraindication. Spironolactone should be considered for symptomatic HFpEF patients with elevated natriuretic peptides. In the near future, trials should target HFrEF patients using exclusion criteria sourced from landmark trials (e.g. severe renal impairment), select more homogeneous HFpEF populations (e.g. with elevated BNP and structural abnormalities on echocardiography), and determine which patients are likely to benefit from MRAs (e.g. according to prespecified biomarkers).

  6. Antiadipogenic effects of the mineralocorticoid receptor antagonist drospirenone: potential implications for the treatment of metabolic syndrome.

    PubMed

    Caprio, Massimiliano; Antelmi, Antonella; Chetrite, Gérard; Muscat, Adeline; Mammi, Caterina; Marzolla, Vincenzo; Fabbri, Andrea; Zennaro, Maria-Christina; Fève, Bruno

    2011-01-01

    The mineralocorticoid receptor (MR) mediates aldosterone- and glucocorticoid-induced adipocyte differentiation. Drospirenone (DRSP) is a potent synthetic antimineralocorticoid with progestogenic and antiandrogenic properties, which is widely used for contraception and hormone replacement therapy. We investigated its potential role on adipocyte differentiation. The effects of DRSP were studied in murine preadipocyte cell lines and primary cultures of human preadipocytes. Differentiation markers and mechanisms underlying phenotypic variations in response to DRSP were explored. Early exposure to DRSP during differentiation led to a marked dose-dependent inhibition of adipose differentiation and triglyceride accumulation in 3T3-L1 and 3T3-F442A cells. DRSP also markedly inhibited adipose conversion of human primary preadipocytes derived from visceral (mesenteric and epicardial) and subcutaneous fat. This effect was MR-dependent and did not involve the glucocorticoid, androgen, or progesterone receptors. DRSP inhibited clonal expansion of preadipocytes and decreased expression of PPARγ, a key transcriptional mediator of adipogenesis, but had no effect on lipolysis, glucose uptake, and PPARγ binding to its ligands. DRSP exerts a potent antiadipogenic effect that is related to an alteration of the transcriptional control of adipogenesis via an antagonistic effect on the MR. Selective MR blockade therefore has promise as a novel therapeutic option for the control of excessive adipose tissue deposition and its related metabolic complications.

  7. Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists

    NASA Astrophysics Data System (ADS)

    Ji, Yongjun; Shu, Mao; Lin, Yong; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Lin, Zhihua

    2013-08-01

    The beta chemokine receptor 5 (CCR5) is an attractive target for pharmaceutical industry in the HIV-1, inflammation and cancer therapeutic areas. In this study, we have developed quantitative structure activity relationship (QSAR) models for a series of 41 azacycles CCR5 antagonists using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA methods. The cross-validated coefficient q2 values of 3D-QASR (CoMFA, CoMSIA, and Topomer CoMFA) methods were 0.630, 0.758, and 0.852, respectively, the non-cross-validated R2 values were 0.979, 0.978, and 0.990, respectively. Docking studies were also employed to determine the most probable binding mode. 3D contour maps and docking results suggested that bulky groups and electron-withdrawing groups on the core part would decrease antiviral activity. Furthermore, docking results indicated that H-bonds and π bonds were favorable for antiviral activities. Finally, a set of novel derivatives with predicted activities were designed.

  8. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist.

    PubMed

    Manglik, Aashish; Kruse, Andrew C; Kobilka, Tong Sun; Thian, Foon Sun; Mathiesen, Jesper M; Sunahara, Roger K; Pardo, Leonardo; Weis, William I; Kobilka, Brian K; Granier, Sébastien

    2012-03-21

    Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

  9. Antagonistic control of a dual-input mammalian gene switch by food additives

    PubMed Central

    Xie, Mingqi; Ye, Haifeng; Hamri, Ghislaine Charpin-El; Fussenegger, Martin

    2014-01-01

    Synthetic biology has significantly advanced the design of mammalian trigger-inducible transgene-control devices that are able to programme complex cellular behaviour. Fruit-based benzoate derivatives licensed as food additives, such as flavours (e.g. vanillate) and preservatives (e.g. benzoate), are a particularly attractive class of trigger compounds for orthogonal mammalian transgene control devices because of their innocuousness, physiological compatibility and simple oral administration. Capitalizing on the genetic componentry of the soil bacterium Comamonas testosteroni, which has evolved to catabolize a variety of aromatic compounds, we have designed different mammalian gene expression systems that could be induced and repressed by the food additives benzoate and vanillate. When implanting designer cells engineered for gene switch-driven expression of the human placental secreted alkaline phosphatase (SEAP) into mice, blood SEAP levels of treated animals directly correlated with a benzoate-enriched drinking programme. Additionally, the benzoate-/vanillate-responsive device was compatible with other transgene control systems and could be assembled into higher-order control networks providing expression dynamics reminiscent of a lap-timing stopwatch. Designer gene switches using licensed food additives as trigger compounds to achieve antagonistic dual-input expression profiles and provide novel control topologies and regulation dynamics may advance future gene- and cell-based therapies. PMID:25030908

  10. Abscisic acid interacts antagonistically with salicylic acid signaling pathway in rice-Magnaporthe grisea interaction.

    PubMed

    Jiang, Chang-Jie; Shimono, Masaki; Sugano, Shoji; Kojima, Mikiko; Yazawa, Katsumi; Yoshida, Riichiro; Inoue, Haruhiko; Hayashi, Nagao; Sakakibara, Hitoshi; Takatsuji, Hiroshi

    2010-06-01

    Plant hormones play pivotal signaling roles in plant-pathogen interactions. Here, we report characterization of an antagonistic interaction of abscisic acid (ABA) with salicylic acid (SA) signaling pathways in the rice-Magnaporthe grisea interaction. Exogenous application of ABA drastically compromised the rice resistance to both compatible and incompatible M. grisea strains, indicating that ABA negatively regulates both basal and resistance gene-mediated blast resistance. ABA markedly suppressed the transcriptional upregulation of WRKY45 and OsNPR1, the two key components of the SA signaling pathway in rice, induced by SA or benzothiadiazole or by blast infection. Overexpression of OsNPR1 or WRKY45 largely negated the enhancement of blast susceptibility by ABA, suggesting that ABA acts upstream of WRKY45 and OsNPR1 in the rice SA pathway. ABA-responsive genes were induced during blast infection in a pattern reciprocal to those of WRKY45 and OsPR1b in the compatible rice-blast interaction but only marginally in the incompatible one. These results suggest that the balance of SA and ABA signaling is an important determinant for the outcome of the rice-M. grisea interaction. ABA was detected in hyphae and conidia of M. grisea as well as in culture media, implying that blast-fungus-derived ABA could play a role in triggering ABA signaling at host infection sites.

  11. Effects of a new cholecystokinin antagonist, TS-941, on experimental acute pancreatitis in rats.

    PubMed

    Wang, Y; Naruse, S; Kitagawa, M; Ishiguro, H; Nakae, Y; Yoshikawa, T; Hayakawa, T

    1998-10-01

    The effects of a new benzodiazepine-derivative, cholecystokinin receptor antagonist, TS-941, on experimental acute pancreatitis were studied in rats. Hemorrhagic pancreatitis was induced by an infusion of a mixture of trypsin and taurocholate into the pancreatic duct. Edematous pancreatitis was induced by intraperitoneal injection of 40 microg/kg body weight of cerulein at 0 and 1 h after the start of the experiment. TS-941 (3 mg/kg) was injected subcutaneously immediately and 3 h after the induction of pancreatitis. In trypsin-taurocholate-induced pancreatitis, TS-941, with or without the synthetic trypsin inhibitor ONO-3403, had no beneficial effects on the survival rate, pancreatic wet weight, and serum pancreatic enzymes. In cerulein-induced pancreatitis, the treatment with TS-941 significantly reduced the increases of pancreatic wet weight and serum amylase and lipase. Plasma trypsinogen activation peptide (TAP) significantly rose 1 h after the first injection of cerulein. TS-941 inhibited the liberation of TAP in cerulein-induced pancreatitis. These results show that TS-941 is effective for prevention of cerulein-induced edematous pancreatitis. ONO-3403 has beneficial effects on trypsin-taurocholate-induced hemorrhagic pancreatitis, but the combination of TS-941 and ONO-3403 has no additive effect.

  12. Nonpeptidic delta (delta) opioid agonists and antagonists of the diarylmethylpiperazine class: what have we learned?

    PubMed

    Calderon, Silvia N

    2011-01-01

    The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of delta-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the delta opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective delta opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the delta opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic delta opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

  13. Antagonistic control of a dual-input mammalian gene switch by food additives.

    PubMed

    Xie, Mingqi; Ye, Haifeng; Hamri, Ghislaine Charpin-El; Fussenegger, Martin

    2014-08-01

    Synthetic biology has significantly advanced the design of mammalian trigger-inducible transgene-control devices that are able to programme complex cellular behaviour. Fruit-based benzoate derivatives licensed as food additives, such as flavours (e.g. vanillate) and preservatives (e.g. benzoate), are a particularly attractive class of trigger compounds for orthogonal mammalian transgene control devices because of their innocuousness, physiological compatibility and simple oral administration. Capitalizing on the genetic componentry of the soil bacterium Comamonas testosteroni, which has evolved to catabolize a variety of aromatic compounds, we have designed different mammalian gene expression systems that could be induced and repressed by the food additives benzoate and vanillate. When implanting designer cells engineered for gene switch-driven expression of the human placental secreted alkaline phosphatase (SEAP) into mice, blood SEAP levels of treated animals directly correlated with a benzoate-enriched drinking programme. Additionally, the benzoate-/vanillate-responsive device was compatible with other transgene control systems and could be assembled into higher-order control networks providing expression dynamics reminiscent of a lap-timing stopwatch. Designer gene switches using licensed food additives as trigger compounds to achieve antagonistic dual-input expression profiles and provide novel control topologies and regulation dynamics may advance future gene- and cell-based therapies.

  14. Novel Fluorine-Containing NMDA Antagonists for Brain Imaging: In Vitro Evaluation

    SciTech Connect

    Alvarado, M.; Biegon, A.

    2001-01-01

    The NMDA receptor has been implicated in neuronal death following stroke, brain injury and neurodegenerative disorders (e.g. Alzheimer's, Parkinson's and Huntington's disease) and in physiological functions (e.g. memory and cognition). Non-competitive antagonists, such as MK- 801 and CNS-1102, that block the action of glutamate at the NMDA receptor have been shown to be neuroprotective by blocking the influx of calcium into the cells. As a result, they are being considered as therapeutic agents for the above mentioned diseases. Several Fluorine-containing novel analogs of NMDA channel blockers have been synthesized and evaluated in search of a compound suitable for 18F labeling and Positron Emission Tomography (PET). Based on in vitro binding assay studies on rat brain membranes, the novel compounds examined displayed a range of affinities. Preliminary analyses indicated that chlorine is the best halogen on the ring, and that ethyl fluoro derivatives are more potent than methyl-fluoro compounds. Further analysis based on autoradiography will be needed to examine the regional binding characteristics of the novel compounds examined in this study. Labeling with 18F will allow the use of these compounds in humans, generating new insights into mechanisms and treatment of diseases involving malfunction of the glutamatergic system in the brain.

  15. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

    PubMed Central

    Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Mathiesen, Jesper M.; Sunahara, Roger K.; Pardo, Leonardo; Weis, William I.; Kobilka, Brian K.; Granier, Sébastien

    2012-01-01

    Summary Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction. PMID:22437502

  16. Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist

    SciTech Connect

    Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Mathiesen, Jesper M.; Sunahara, Roger K.; Pardo, Leonardo; Weis, William I.; Kobilka, Brian K.; Granier, Sébastien

    2012-06-27

    Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled {mu}-opioid receptor ({mu}-OR) in the central nervous system. Here we describe the 2.8 {angstrom} crystal structure of the mouse {mu}-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the {mu}-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

  17. Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?

    NASA Astrophysics Data System (ADS)

    Calderon, Silvia N.

    The discovery of the selective delta (δ) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of δ-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the δ opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective δ opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the δ opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic δ opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

  18. The role of renal hemodynamics in the antihypertensive action of mepirodipine, a new calcium antagonist.

    PubMed

    Noda, H; Fujita, T; Ogata, E

    1992-01-01

    To evaluate the role of regional hemodynamics in the anti-hypertensive effect of mepirodipine, a new dihydropyridine-derivative calcium antagonist, we measured systemic, renal, hepatic, and forearm hemodynamics in 10 patients with essential hypertension treated with mepirodipine (15 mg/day) for 4 weeks. After the administration of mepirodipine, a significant decline in mean blood pressure (-13.8 +/- 2.3%, p less than 0.01) accompanied by a decrease in systemic vascular resistance (-21.1 +/- 2.6%, p less than 0.01) was observed. Although forearm vascular resistance did not change significantly, both renal (-19.2 +/- 6.7%, p less than 0.01) and hepatic vascular resistance (-17.6 +/- 3.8%, p less than 0.01) decreased considerably. The decrements of mean blood pressure with mepirodipine did not correlate with those of hepatic or forearm vascular resistance but correlated positively with those of renal vascular resistance (r = 0.699, p less than 0.05). Moreover, the increment of renal blood flow with mepirodipine was negatively correlated with the pretreatment level of renal blood flow (r = -0.670, p less than 0.05); renal blood flow increased to a greater extent in patients with lower pretreatment renal blood flow. These findings suggest that the oral administration of mepirodipine in patients with essential hypertension can produce selective vasodilation in the renal vasculature, which may play an important role in the relatively long-term antihypertensive effect of this drug.

  19. Structure-activity studies on 1,4-dihydropyridine calcium channel antagonists and activators

    SciTech Connect

    Joslyn, A.F.

    1986-01-01

    Four series of 1,4-dihydropyridine Ca{sup 2+} channel antagonists related to mifedipine were synthesized by a modified Hantzsch procedure to determine the effects of ester (C{sub 3} = CO{sub 2}Me, C{sub 5} = CO{sub 2}R) and phenyl (C{sub 4}) substituents on pharmacological and radioligand binding ((H)nitrendipine) activities in guinea pig ileal longitudinal smooth muscle. Two series of Ca{sup 2+} channel activator 1,4-dihydropyridines, BAY K 8644 (C{sub 3} = NO{sub 2}, C{sub 5} = CO{sub 2}Me) and CGP 28392 (C{sub 2,3} = lactone, C{sub 5} = CO{sub 2}Me) were biochemically evaluated by inhibition of ({sup 3}H)nitrendipine binding in guinea pig ileal longitudinal smooth muscle membranes to establish fundamental structure-activity requirements. A homologous series of bis-1,4-dihydropyridines were synthesized, pharmacologically and biochemically evaluated in an attempt to explore the distribution of the 1,4-dihydropyridine receptor in guinea pig ileal longitudinal smooth muscle membranes. Several potential affinity labels including ester substituted 3- and 4-fluorosulfonyl benzoyl and isothiocyanate derivatives were synthesized and evaluated by inhibition of ({sup 3}H)nitrendipine binding.

  20. Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells.

    PubMed

    Liu, Jing; He, Chengwei; Zhou, Keyuan; Wang, Jingdong; Kang, Jing X

    2009-01-09

    Estrogen receptor (ER) antagonists have been widely used for breast cancer treatment, but the efficacy and drug resistance remain to be clinical concerns. The purpose of this study was to determine whether the extracts of coptis, an anti-inflammatory herb, improve the anticancer efficacy of ER antagonists. The results showed that the combined treatment of ER antagonists and the crude extract of coptis or its purified compound berberine conferred synergistic growth inhibitory effect on MCF-7 cells (ER+), but not on MDA-MB-231 cells (ER-). Similar results were observed in the combined treatment of fulvestrant, a specific aromatase antagonist. Analysis of the expression of breast cancer related genes indicated that EGFR, HER2, bcl-2, and COX-2 were significantly downregulated, while IFN-beta and p21 were remarkably upregulated by berberine. Our results suggest that coptis extracts could be promising adjuvant to ER antagonists in ER positive breast cancer treatment through regulating expression of multiple genes.

  1. Identification of overlapping but differential binding sites for the high-affinity CXCR3 antagonists NBI-74330 and VUF11211.

    PubMed

    Scholten, Danny J; Roumen, Luc; Wijtmans, Maikel; Verkade-Vreeker, Marlies C A; Custers, Hans; Lai, Michael; de Hooge, Daniela; Canals, Meritxell; de Esch, Iwan J P; Smit, Martine J; de Graaf, Chris; Leurs, Rob

    2014-01-01

    CXC chemokine receptor CXCR3 and/or its main three ligands CXCL9, CXCL10, and CXCL11 are highly upregulated in a variety of diseases. As such, considerable efforts have been made to develop small-molecule receptor CXCR3 antagonists, yielding distinct chemical classes of antagonists blocking binding and/or function of CXCR3 chemokines. Although it is suggested that these compounds bind in an allosteric fashion, thus far no evidence has been provided regarding the molecular details of their interaction with CXCR3. Using site-directed mutagenesis complemented with in silico homology modeling, we report the binding modes of two high-affinity CXCR3 antagonists of distinct chemotypes: VUF11211 [(S)-5-chloro-6-(4-(1-(4-chlorobenzyl)piperidin-4-yl)-3-ethylpiperazin-1-yl)-N-ethylnicotinamide] (piperazinyl-piperidine) with a rigid elongated structure containing two basic groups and NBI-74330 [(R)-N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(pyridin-3-ylmethyl)acetamide] (8-azaquinazolinone) without any basic group. Here we show that NBI-74330 is anchored in the transmembrane minor pocket lined by helices 2 (W2.60, D2.63), 3 (F3.32), and 7 (S7.39, Y7.43), whereas VUF11211 extends from the minor pocket into the major pocket of the transmembrane domains, located between residues in helices 1 (Y1.39), 2 (W2.60), 3 (F3.32), 4 (D4.60), 6 (Y6.51), and 7 (S7.39, Y7.43). Mutation of these residues did not affect CXCL11 binding significantly, confirming the allosteric nature of the interaction of these small molecules with CXCR3. Moreover, the model derived from our in silico-guided studies fits well with the already published structure-activity relationship data on these ligands. Altogether, in this study, we show overlapping, yet different binding sites for two high-affinity CXCR3 antagonists, which offer new opportunities for the structure-based design of allosteric modulators for CXCR3.

  2. Design and synthesis of (ant)-agonists that alter appetite and adiposity.

    PubMed

    Van der Ploeg, Lex H T; Kanatani, Akio; MacNeil, Douglas; Ming Fong, Tung; Strack, Alison; Nargund, Ravi; Guan, Xiao-Ming

    2006-01-01

    Over the past decade, hypothalamic circuits have been described that impact energy homeostasis in rodents and humans. Our drug development efforts for the treatment of obesity and the metabolic syndrome have largely focused on selected genetic and/or pharmacologically validated pathways. The translation of these pathways into therapeutics for the treatment of obesity will find its first clinical successes over the coming decade. Initial efforts have focused on gaining a better understanding of the relevance of rodent pharmacological and genetic observations for the development of therapeutics for the treatment of human obesity. We pursue pathways defined by the expression of the ghrelin receptor, melanin-concentrating hormone receptors, melanocortin receptors, cannabinoid receptors and neuropeptide Y1 and Y5 receptors. In this review, we will discuss drug development efforts for the treatment of obesity, focused on selective melanocortin 4 receptor agonists and neuropeptide Y1 and Y5 receptor antagonists. These drug development efforts required an in-depth understanding of cell-based observations which drive the development of compound structure-activity relationships. These include understanding of receptor function in selected cell-based backgrounds and early evaluation and validation of ex vivo observations in appropriate in vivo models. In order to develop selective and safe anti-obesity drugs, diverse approaches are needed to increase the likelihood of clinical success, including: (i) developing a detailed understanding of the predictive value of rodent pathways for treatment of human disease; (ii) knowledge of the exact location of targeted receptor subtypes for the clinical indication under study in order to derive a suitable compound profile; (iii) predictive measures of in vivo and/or ex vivo receptor occupancy required to bring about a desired physiological effect; (iv) predictive parameters that outline that the drug-derived effects are safe and

  3. Thermodynamic analysis of agonist and antagonist binding to the chicken brain melatonin receptor.

    PubMed Central

    Chong, N. W.; Sugden, D.

    1994-01-01

    1. The binding of 2-[125I]-iodomelatonin to chicken brain membranes, and the inhibition of binding by melatonin, N-acetyltryptamine and luzindole, were examined at temperatures between 4 degrees C and 37 degrees C. 2. At all temperatures studied, the binding affinity (Kd or Ki) for 2-[125I]-iodomelatonin, melatonin (both agonists) and, to a lesser extent, N-acetyltryptamine (a partial agonist) was reduced by inclusion of guanosine triphosphate (GTP, 1 mM) in the assay. GTP did not affect the Ki for luzindole, a melatonin receptor antagonist. 3. The maximal density of binding sites (Bmax) was not affected by temperature but the Kd showed a peak at 21 degrees C with lower values at both higher and lower temperatures giving curvilinear van't Hoff plots (lnKA vs l/temperature). 4. Derived changes in entropy (delta S degree) and enthalpy (delta H degree) of binding for all of the melatonin ligands decreased as temperature increased. 5. The affinity, and thus the free energy of binding, delta G degree, of these ligands at the melatonin receptor have identical values at several temperatures yet at these temperatures delta S degree and delta H degree were very different, implying that more than one intermolecular force must be involved in the binding of ligand and receptor. 6. Conceivably, the large positive delta S degree observed at low temperatures, perhaps as a result of hydrophobic interactions, is compensated by a corresponding, but opposite, change in enthalpy at higher temperatures. However, it is not clear what type of binding force(s) would show such a temperature-dependence. 7. These studies suggest that caution must be exercised in the molecular interpretation of derived measures of delta S degree and delta H degree obtained from direct measurements of delta G degree. PMID:8012710

  4. The identification of a series of novel, soluble non-peptidic neuropeptide Y Y2 receptor antagonists.

    PubMed

    Lunniss, Gillian E; Barnes, Ashley A; Barton, Nick; Biagetti, Matteo; Bianchi, Federica; Blowers, Stephen M; Caberlotto, Laura L; Emmons, Amanda; Holmes, Ian P; Montanari, Dino; Norris, Roz; Puckey, Gemma V; Walters, Dewi J; Watson, Steve P; Willis, John

    2010-12-15

    The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonist with enhanced CNS exposure.

  5. The NK1 receptor antagonist L822429 reduces heroin reinforcement.

    PubMed

    Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus

    2013-05-01

    Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

  6. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists.

    PubMed

    Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

    2016-01-01

    Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and

  7. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    PubMed Central

    Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

    2016-01-01

    Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and

  8. Distribution of forces between synergistics and antagonistics muscles using an optimization criterion depending on muscle contraction behavior.

    PubMed

    Rengifo, Carlos; Aoustin, Yannick; Plestan, Franck; Chevallereau, Christine

    2010-04-01

    In this paper, a new neuromusculoskeletal simulation strategy is proposed. It is based on a cascade control approach with an inner muscular-force control loop and an outer joint-position control loop. The originality of the work is located in the optimization criterion used to distribute forces between synergistic and antagonistic muscles. The cost function and the inequality constraints depend on an estimation of the muscle fiber length and its time derivative. The advantages of a such criterion are exposed by theoretical analysis and numerical tests. The simulation model used in the numerical tests consists in an anthropomorphic arm model composed by two joints and six muscles. Each muscle is modeled as a second-order dynamical system including activation and contraction dynamics. Contraction dynamics is represented using a classical Hill's model.

  9. Synthesis of analogues of the Des-Phe-NH2 C-terminal hexapeptide of cholecystokinin showing gastrin antagonist activity.

    PubMed

    Laur, J; Rodriguez, M; Aumelas, A; Bali, J P; Martinez, J

    1986-04-01

    Four analogues of Z-CCK-27-32-NH2, Z-Tyr(SO3-)-Met-Gly-Trp-Met-Asp-NH2, a cholecystokinin receptor antagonist have been synthesized by solution methodology. In these analogues, Z-Tyr(SO3-)-Nle-Gly-Trp-Met-Asp-NH2 16, Z-Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-NH2 17, BOC-Tyr(SO3-)-Met-Gly-Trp-Met-Asp-NH2 24 and Boc-Tyr(SO3-)-Met-Gly-Trp-Nle-Asp-NH2 25 methionyl residues were replaced by norleucyl residues. Preliminary biological activity on gastrin-induced acid secretion, in rat, are reported. These derivatives proved to antagonize the action of gastrin, with ED 50 of between 0.5 and 3 mg/kg.

  10. Galanin receptor antagonists : a potential novel pharmacological treatment for mood disorders.

    PubMed

    Ogren, Sven Ove; Kuteeva, Eugenia; Hökfelt, Tomas; Kehr, Jan

    2006-01-01

    functional activity. In addition, galanin produces a functional blockade of postsynaptic 5-HT1A receptor-mediated responses. Both pharmacological and genetic studies suggest a role for galanin in depression-like behaviour in rodent models. Transgenic mice overexpressing galanin under the control of the platelet-derived growth factor-beta promoter display increased immobility in the forced swim test. Intracerebroventricular administration of galanin in the rat increases depression-like behaviour, and this is fully blocked by the nonselective peptide galanin receptor antagonist M35. Importantly, M35 alone administered intracerebroventricularly produces an antidepressant-like effect. Recently, newly developed receptor-specific nonpeptidergic galanin GAL3 receptor antagonists (SNAP-37889 and SNAP-398299), which cross the blood-brain barrier after systemic administration, have shown antidepressant-like activity in several animal models. On the other hand, stimulation of the GAL2 receptor at the raphe level by local application of the GAL2 receptor agonist galanin (2-11) has been shown to increase serotonin levels in the hippocampus and dorsal raphe. These results indicate an important (mainly inhibitory) role of galanin as a regulator of brain serotonin and 5-HT1A receptor-mediated transmission, which may be of potential importance for understanding mood disorders and for the development of antidepressant drugs. Taken together, the present evidence suggests that antidepressant efficacy may be associated with compounds acting as antagonists at the GAL3 and/or possibly GAL1 receptors, and/or agonists at the GAL2 receptor.

  11. Effect of calmodulin antagonists on the growth and graviresponsiveness of primary roots of maize.

    PubMed

    Stinemetz, C L; Hasenstein, K H; Young, L M; Evans, M L

    1992-11-01

    We examined the effect of calmodulin (CaM) antagonists applied at the root tip on root growth, gravity-induced root curvature, and the movement of calcium across the root tip and auxin (IAA) across the elongation zone of gravistimulated roots. All of the CaM antagonists used in these studies delayed gravity-induced curvature at a concentration (1 micromole) that did not affect root growth. Calmodulin antagonists (> or = 1 micromole) inhibited downward transport of label from 45Ca2+ across the caps of gravistimulated roots relative to the downward transport of 45Ca2+ in gravistimulated roots which were not treated with CaM antagonists. Application of CaM antagonists at the root tip (> or = 1 micromole) also decreased the relative downward movement of label from 3H-IAA applied to the upper side of the elongation zone of gravistimulated roots. In general, tip application of antagonists inhibited neither the upward transport of 45Ca2+ in the root tip nor the upward movement of label from 3H-IAA in the elongation zone of gravistimulated roots. Thus, roots treated with CaM antagonists > or = 1 micromole become less graviresponsive and exhibit reduced or even a reversal of downward polarity of calcium transport across the root tip and IAA transport across the elongation zone. The results indicate that calmodulin-regulated events play a role in root gravitropism.

  12. Effect of calmodulin antagonists on the growth and graviresponsiveness of primary roots of maize

    NASA Technical Reports Server (NTRS)

    Stinemetz, C. L.; Hasenstein, K. H.; Young, L. M.; Evans, M. L.

    1992-01-01

    We examined the effect of calmodulin (CaM) antagonists applied at the root tip on root growth, gravity-induced root curvature, and the movement of calcium across the root tip and auxin (IAA) across the elongation zone of gravistimulated roots. All of the CaM antagonists used in these studies delayed gravity-induced curvature at a concentration (1 micromole) that did not affect root growth. Calmodulin antagonists (> or = 1 micromole) inhibited downward transport of label from 45Ca2+ across the caps of gravistimulated roots relative to the downward transport of 45Ca2+ in gravistimulated roots which were not treated with CaM antagonists. Application of CaM antagonists at the root tip (> or = 1 micromole) also decreased the relative downward movement of label from 3H-IAA applied to the upper side of the elongation zone of gravistimulated roots. In general, tip application of antagonists inhibited neither the upward transport of 45Ca2+ in the root tip nor the upward movement of label from 3H-IAA in the elongation zone of gravistimulated roots. Thus, roots treated with CaM antagonists > or = 1 micromole become less graviresponsive and exhibit reduced or even a reversal of downward polarity of calcium transport across the root tip and IAA transport across the elongation zone. The results indicate that calmodulin-regulated events play a role in root gravitropism.

  13. Survey of H2-antagonist usage in acute upper gastrointestinal hemorrhage.

    PubMed

    Bhatt, B D; Meriano, F V; Phipps, T L; Ho, H; Zuckerman, M J

    1990-02-01

    H2-antagonists are frequently used in the management of upper gastrointestinal (UGI) hemorrhage despite their lack of proven efficacy. In order to determine the pattern of H2-antagonist usage for this indication, we retrospectively reviewed the charts of 137 patients admitted with acute UGI bleeding over a 1-year period at two teaching hospitals in West Texas. An H2-antagonist was ordered in 89% of patients (77%) intravenous, 12% oral). It was administered within 2 h of admission in 25% of these patients, within 4 h in 54%, and within 8 h in 78%. An H2-antagonist was ordered among the initial six orders in 49% and among the initial 10 orders in 77% of patients. Considering orders for specific therapies, an H2-antagonist was in the initial three orders in 60% of patients and among the initial six orders in 97%. Of the patients who were prescribed an H2-antagonist and who also had upper endoscopy, the drug was ordered prior to endoscopy in 86%. This review of H2-antagonist usage in the management of acute UGI bleeding has identified a prescribing pattern of writing for these drugs early in the sequence of order writing, with the drugs being given early in the course of hospitalization.

  14. [Distribution and characteristics of soil antagonistic actinomycetes on northern slope of Taibai Mountain, Qinling].

    PubMed

    Zhu, Wen-Jie; Xue, Quan-Hong; Cao, Yan-Ru; Xue, Lei; Shen, Guang-Hui; Lai, Hang-Xian

    2011-11-01

    Twelve representative soil samples were collected from different altitudes on the northern slope of Taibai Mountain to study the distribution and characteristics of soil antagonistic actinomyces by using agar block method. There existed a great deal of soil antagonistic actinomyces in the study area. Among the 141 actinomycete strains isolated, 116 strains (82.3%) showed antagonism toward 12 target bacteria or fungi. The antagonistic strains at altitudes 800-1845, 3488, 3655, and 3670 m occupied 73.7% -86.8%, 81.3%, 78.9% and 82.3% of the total, respectively. 42.1% of the strains at altitudes 1200-2300 m and > 3400 m showed strong and broad spectrum antagonistic activity, suggesting that there was a great potential for the isolation of actinomycete strains with strong anti-biotic capability at these altitudes. 24.1% of the antagonistic actinomycetes showed antagonism against Staphyloccocus aureu, and 2.4%, 6.9% and 11.2% of them showed activity toward Verticillium dahliae in cotton, Phytophthora sp. in strawberry and Neonectria radiciccla in ginseng, respectively. This study showed that the soil actinomycete antagonistic potentiality (SAAP) could be used as a quantitative indicator to evaluate the potential of antagonistic actinomycete resources in soil.

  15. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    PubMed Central

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M.; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  16. Pharmacological evaluation of IQM-95,333, a highly selective CCKA receptor antagonist with anxiolytic-like activity in animal models

    PubMed Central

    Ballaz, Santiago; Barber, Ana; Fortuño, Ana; Del Río, Joaquín; Martín-Martínez, Mercedes; Gómez-Monterrey, Isabel; Herranz, Rosario; González-Muñiz, Rosario; García-López, Maria-Teresa

    1997-01-01

    The pyridopyrimidine derivative IQM-95,333 ((4aS,5R)-2-benzyl-5-[Nα-tert-butoxicarbonyl)L-tryptophyl]amino-1,3dioxoperhydropyrido[1,2-c]pyrimidine), a new non-peptide antagonist of cholecystokinin type A (CCKA) receptors, has been evaluated in vitro and in vivo in comparison with typical CCKA and CCKB receptor antagonists, such as devazepide, lorglumide, L-365,260 and PD-135,158. IQM-95,333 displaced [3H]-CCK-8S binding to CCKA receptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCKB receptors was negligible (IC50>10 μM). IQM-95,333 was a more selective CCKA receptor ligand than devazepide and other CCKA receptor antagonists. Like devazepide, IQM-95,333 was a more potent antagonist of CCK-8S- than of CCK-4-induced contraction of the longitudinal muscle from guinea-pig ileum, suggesting selective antagonism at CCKA receptors. IQM-95,333 and devazepide were also potent inhibitors of CCK-8S-stimulated amylase release from isolated pancreatic acini, a CCKA receptor-mediated effect. The drug concentrations required (IC50s around 20 nM) were higher than in binding studies to pancreas homogenates. Low doses (50–100 μg kg−1, i.p.) of IQM-95,333 and devazepide, without any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration of CCK-8S, two effects associated with stimulation of peripheral CCKA receptors. IQM-95,333 showed an anxiolytic-like profile in the light/dark exploration test in mice over a wide dose range (10–5,000 μg kg−1). Typical CCKA and CCKB antagonists, devazepide and L-365,260 respectively, were only effective within a more limited dose range. In a classical conflict paradigm for the study of anxiolytic drugs, the punished-drinking test, IQM-95,333, devazepide and L-365,260 were effective within a narrow dose range. The dose-response curve for the three drugs was biphasic, suggesting that

  17. Bcl-2 Antagonists: A Proof of Concept for CLL Therapy

    PubMed Central

    Balakrishnan, Kumudha; Gandhi, Varsha

    2014-01-01

    Defective apoptosis is a fundamental hallmark feature of CLL biology and is a major target of cancer therapy development. High levels of Bcl-2 family anti-apoptotic proteins are considered primarily responsible for inhibiting apoptosis in CLL cells. While several approaches were considered to selectively inhibit Bcl-2 family anti-apoptotic proteins, the discovery that gossypol binds and antagonizes anti-apoptotic effect of Bcl-2 family proteins was a major breakthrough in identifying specific Bcl-2 antagonists. The concept of mimicking BH3 domain emphasized the importance of Bcl-2 family-targeted therapy that can modulate the function of anti-apoptotic proteins. Although parent compound gossypol did not sustain in the clinic, its structural modifications led to the development of additional analogues that demonstrated improved efficacy and reduced toxicity in preclinical and clinical investigations. Proof of concept of this hypothesis was demonstrated by structure based BH3 mimetic ABT-737 that has shown greater cytotoxicity towards CLL cells both in pre-clinical models and clinical trials. Its oral compound ABT-263 has demonstrated the substantial susceptibility of chronic lymphocytic leukemia cells through Bcl-2 inhibition. Collectively, results of a Phase I Study of Navitoclax (ABT-263) in patients with relapsed or refractory disease warrants Bcl-2 as a valid therapeutic target in CLL. Importantly, molecules that mimic pro-apoptotic BH3 domains represent a direct approach to overcoming the protective effects of anti-apoptotic proteins such as Mcl-1, Bcl-2 and Bcl-XL. PMID:23907405

  18. [Vascular calcifications, the hidden side effects of vitamin K antagonists].

    PubMed

    Bennis, Youssef; Vengadessane, Subashini; Bodeau, Sandra; Gras, Valérie; Bricca, Giampiero; Kamel, Saïd; Liabeuf, Sophie

    2016-09-01

    Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA.

  19. Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

    PubMed

    Hong, Seoung-Soo; Bavadekar, Supriya A; Lee, Sang-Il; Patil, Popat N; Lalchandani, S G; Feller, Dennis R; Miller, Duane D

    2005-11-01

    The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

  20. Major Depressive Disorder and Kappa Opioid Receptor Antagonists

    PubMed Central

    Li, Wei; Sun, Huijiao; Chen, Hao; Yang, Xicheng; Xiao, Li; Liu, Renyu; Shao, Liming; Qiu, Zhuibai

    2016-01-01

    Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine reuptake inhibitor (SNRIs) for this condition have been widely accepted, but they were challenged by unacceptable side-effects, potential drug-drug interactions (DDIs) or slow onset/lack of efficacy. The endogenous opioid system is involved in stress and emotion regulatory processes and its role in MDD has been implicated. Although several KOR antagonists including JDTic and PF-04455242 were discontinued in early clinical trials, ALKS 5461 and CERC-501(LY-2456302) survived and entered into Phase-III and Phase-II trials, respectively. Considering the efficacy and safety of early off-label use of buprenorphine in the management of the treatment-resistant depression (TRD), it will be not surprising to predict the potential success of ALKS 5461 (a combination of buprenorphine and ALKS-33) in the near future. Moreover, CERC-501 will be expected to be available as monotherapy or adjuvant therapy with other first-line antidepressants in the treatment of TRD, if ongoing clinical trials continue to provide positive benefit-risk profiles. Emerging new researches might bring more drug candidates targeting the endogenous opioid system to clinical trials to address current challenges in MDD treatment in clinical practice. PMID:27213169

  1. Side Effects of Leukotriene Receptor Antagonists in Asthmatic Children

    PubMed Central

    Erdem, Semiha Bahceci; Nacaroglu, Hikmet Tekin; Unsal Karkiner, Canan Sule; Gunay, Ilker; Can, Demet

    2015-01-01

    Background: Leukotriene receptor antagonists (LTRAs) are drugs which have been widely used more than ten years. As the use of LTRAs increases, our knowledge with respect to their side effects increases as well. Objectives: The objective of our study was to evaluat the observed side effects of LTRAs used in patients with astma. Patients and Methods: 1024 patients treated only with LTRAs owing to asthma or early wheezing were included in the study for a five-year period. The observed side effects of LTRAs in these patients were retrospectively investigated. The side effects were divided into two parts as psychiatric and non-psychiatric. Results: Among the 1024 cases included in the study, 67.5% of the patients out of 41 with side effects were male, 32.5% were female and the average age was 6.5 years. The rate of patients with asthma was 63.41% and 36.58% of the patients had early wheezing. It was determined that sex, age and diagnosis (early wheezing or asthma) of the patients were ineffective in the emergence of side effects. The average period for the emergence of side effects was the first month. It was observed that hyperactivity was the most frequently observed psychiatric side effect and that abdominal pain was the non-psychiatric side effect. Conclusions: The side effects of LTRAs were common in children. Therefore, patients must be informed at the beginning of the treatment and they must be evaluated at certain intervals. PMID:26495098

  2. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    SciTech Connect

    Donlon, M.A.; Melia, J.A.; Helgeson, E.A.; Wolfe, W.W.

    1986-03-01

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor.

  3. Vasopressin receptor antagonists and their role in clinical medicine

    PubMed Central

    Narayen, Girish; Mandal, Surya Narayan

    2012-01-01

    Hyponatremia is the most common electrolyte abnormality in hospitalized patients. Its treatment is based not only on extracellular fluid volume status of patients but also on its pathogenetic mechanisms. Conventional treatment of hyponatremia like fluid restriction, which is useful in euvolemic and hypervolemic hyponatremia, has very poor patient compliance over long term. Vasopressin receptor antagonists (Vaptans) are a new group of nonpeptide drugs which have been used in various clinical conditions with limited success. Whereas conivaptan is to be administered intravenously, the other vaptans like tolvaptan, lixivaptan, and satavaptan are effective as oral medication. They produce aquaresis by their action on vasopressin type 2 (V2R) receptors in the collecting duct and thus increase solute free water excretion. Vaptans are being used as an alternative to fluid restriction in euvolemic and hypervolemic hyponatremic patients. Efficacy of vaptans is now well accepted for management of correction of hyponatremia over a short period. However, its efficacy in improving the long-term morbidity and mortality in patients with chronic hyponatremia due to cirrhosis and heart failure is yet to be established. Vaptans have not become the mainstay treatment of hyponatremia yet. PMID:22470853

  4. Signatures of Sex-Antagonistic Selection on Recombining Sex Chromosomes

    PubMed Central

    Kirkpatrick, Mark; Guerrero, Rafael F.

    2014-01-01

    Sex-antagonistic (SA) selection has major evolutionary consequences: it can drive genomic change, constrain adaptation, and maintain genetic variation for fitness. The recombining (or pseudoautosomal) regions of sex chromosomes are a promising setting in which to study SA selection because they tend to accumulate SA polymorphisms and because recombination allows us to deploy the tools of molecular evolution to locate targets of SA selection and quantify evolutionary forces. Here we use coalescent models to characterize the patterns of polymorphism expected within and divergence between recombining X and Y (or Z and W) sex chromosomes. SA selection generates peaks of divergence between X and Y that can extend substantial distances away from the targets of selection. Linkage disequilibrium between neutral sites is also inflated. We show how the pattern of divergence is altered when the SA polymorphism or the sex-determining region was recently established. We use data from the flowering plant Silene latifolia to illustrate how the strength of SA selection might be quantified using molecular data from recombining sex chromosomes. PMID:24578352

  5. Calcium antagonists. A role in the management of cyanide poisoning

    SciTech Connect

    Maduh, E.U.; Porter, D.W.; Baskin, S.I.

    1993-12-31

    The physiological role of calcium was demonstrated by Ringer (1883) when he linked the omission of calcium (Ca++) from the bathing medium to the induction of cardiac arrest in the isolated frog heart. This observation established that Ca++ controlled muscle contraction but it was not until the autumn of 1963 that the specific pharmacological significance of this contribution was realised by Fleckenstein (1964), leading to the development of Ca++ antagonism as a concept in drug action (Fleckenstein 1977). Identifying the precise role of Ca++ ions in toxic cell injury and tissue death attributable to drug and chemical intoxication has lagged behind developments in Ca++ physiology and pharmacology and to date, much remains to be learned, although studies aimed at characterising the role of Ca++ in cytotoxic cell injury are receiving intense attention (Bondy Komulainen 1988; Maduh et al. l988a, l99Oa,b; Orrenius et al. 1989; Trump et al. 1989). On the other hand, the importance of cyanide as a poison has been known from antiquity (for references to earlier literature see Baskin Fricke 1992; Solomonson 1981). In experimental cyanide poisoning, recent studies have examined alterations in cell Ca++ and the influence of Ca++ antagonists in the management of this chemical toxicological emergency. These efforts have principally focused on the cellular Ca++ homeostasis system, its interrelationship with cellular components, and its susceptibility to cyanide action.

  6. A new class of NO-donor H3-antagonists.

    PubMed

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Marini, Elisabetta; Rolando, Barbara; Sorba, Giovanni; Fruttero, Roberta; Gasco, Alberto

    2004-05-01

    Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 microM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier.

  7. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton.

    PubMed

    Gordon, Keith E; Kinnaird, Catherine R; Ferris, Daniel P

    2013-04-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to "fight" the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations.

  8. Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy.

    PubMed

    Roscioni, Sara S; de Zeeuw, Dick; Bakker, Stephan J L; Lambers Heerspink, Hiddo J

    2012-12-01

    Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients older than 65 years with impaired kidney function, and/or diabetes. Patients with these characteristics might still benefit from MRA therapy, however, and should not be excluded from this treatment option. This limitation raises the question of how to optimize the therapeutic use of MRAs in this population of patients. Understanding the individual variability in patients' responses to MRAs, in terms of albuminuria, blood pressure and serum potassium levels, might lead to targeted intervention. MRA use might be restricted to patients with high levels of mineralocorticoid activity, evaluated by circulating renin and aldosterone levels or renal excretion of potassium. In addition, reviewing the patient's diet and concomitant medications might prove useful in reducing the risk of developing subsequent hyperkalaemia. If hyperkalaemia does develop, treatment options exist to decrease potassium levels, including administration of calcium gluconate, insulin, β(2)-agonists, diuretics and cation-exchange resins. In combination with novel aldosterone blockers, these strategies might offer a rationale with which to optimize therapeutic intervention and extend the population of patients who can benefit from use of MRAs.

  9. Orexin receptor antagonists as therapeutic agents for insomnia

    PubMed Central

    Equihua, Ana C.; De La Herrán-Arita, Alberto K.; Drucker-Colin, Rene

    2013-01-01

    Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia. PMID:24416019

  10. Spatial working memory in rats: effects of monoaminergic antagonists.

    PubMed

    Beatty, W W; Rush, J R

    1983-01-01

    To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25-1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10-20 mg/kg), phentolamine (5-20 mg/kg) or methysergide (5-15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.

  11. Effect of antagonist muscle fatigue on knee extension torque.

    PubMed

    Beltman, J G M; Sargeant, A J; Ball, D; Maganaris, C N; de Haan, A

    2003-09-01

    The effect of hamstring fatigue on knee extension torque was examined at different knee angles for seven male subjects. Before and after a dynamic flexion fatigue protocol (180 degrees s(-1), until dynamic torque had declined by 50%), maximal voluntary contraction extension torque was measured at four knee flexion angles (90 degrees, 70 degrees, 50 degrees and 30 degrees ). Maximal torque generating capacity and voluntary activation of the quadriceps muscle were determined using electrical stimulation. Average rectified EMG of the biceps femoris was determined. Mean dynamic flexion torque declined by 48+/-11%. Extensor maximal voluntary contraction torque, maximal torque generating capacity, voluntary activation and average rectified EMG at the four knee angles were unaffected by the hamstring fatigue protocol. Only at 50 degrees knee angle was voluntary activation significantly lower (15.7%) after fatigue ( P<0.05). In addition, average rectified EMG before fatigue was not significantly influenced by knee angle. It was concluded that a fatigued hamstring muscle did not increase the maximal voluntary contraction extension torque and knee angle did not change coactivation. Three possible mechanisms may explain the results: a potential difference in recruited fibre populations in antagonist activity compared with the fibres which were fatigued in the protocol, a smaller loss in isometric torque generating capacity of the hamstring muscle than was expected from the dynamic measurements and/or a reduction in voluntary activation.

  12. Effects of cholecystokinin receptor antagonist loxiglumide on rat exocrine pancreas.

    PubMed

    Nakano, S; Tachibana, I; Otsuki, M

    1994-07-01

    Effects of long-term administration of the cholecystokinin receptor antagonist loxiglumide on exocrine pancreas were studied in adult rats. Plasma concentrations of loxiglumide at 8 h after a single subcutaneous injection of 50 mg/kg body weight of loxiglumide were 3.2 +/- 0.8 microgram/ml, which were comparable to those at 12 h after oral administration of the same dose (3.7 +/- 0.9 microgram/ml). Eight hours' prior subcutaneous injection of loxiglumide (50 mg/kg body weight) significantly suppressed pancreatic exocrine secretion stimulated by an intravenous bolus injection of 50 ng/kg body weight caerulein compared with the control rats. Based on these results, in the first experiment, loxiglumide at a dose of 50 mg/kg body weight was given subcutaneously three times a day (low dose) for 6 days to adult rats fed a standard laboratory diet. Low dose of loxiglumide significantly decreased pancreatic wet weight (-14%) and pancreatic contents of protein (-26%), trypsin (-38%), and lipase (-68%), while having no significant effect on pancreatic contents of DNA and amylase. In the second experiment, three times higher dose of loxiglumide (150 mg/kg body weight) was given by an orogastric tube twice daily for 6 days. High dose of loxiglumide significantly decreased pancreatic weight (-11%) and contents of protein (-20%) and DNA (-22%), whereas it significantly increased amylase (+92%) and trypsin content (+20%).(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Antagonistic evolution in an aposematic predator-prey signaling system.

    PubMed

    Speed, Michael P; Franks, Daniel W

    2014-10-01

    Warning signals within species, such as the bright colors of chemically defended animals, are usually considered mutualistic, monomorphic traits. Such a view is however increasingly at odds with the growing empirical literature, showing nontrivial levels of signal variation within prey populations. Key to understanding this variation, we argue, could be a recognition that toxicity levels frequently vary within populations because of environmental heterogeneity. Inequalities in defense may undermine mutualistic monomorphic signaling, causing evolutionary antagonism between loci that determine appearance of less well-defended and better defended prey forms within species. In this article, we apply a stochastic model of evolved phenotypic plasticity to the evolution of prey signals. We show that when toxicity levels vary, then antagonistic interactions can lead to evolutionary conflict between alleles at different signaling loci, causing signal evolution, "red queen-like" evolutionary chase, and one or more forms of signaling equilibria. A key prediction is that variation in the way that predators use information about toxicity levels in their attack behaviors profoundly affects the evolutionary characteristics of the prey signaling systems. Environmental variation is known to cause variation in many qualities that organisms signal; our approach may therefore have application to other signaling systems.

  14. Alvimopan: a peripherally acting mu-opioid receptor antagonist.

    PubMed

    Leslie, John B

    2007-09-01

    Postoperative ileus (POI), a transient cessation of coordinated bowel motility after surgery, is an important factor in extending the length of hospital stay. The etiology of POI is multifactorial, and related to both the surgical and anesthetic pathways chosen. Additionally, opioids used to manage non-cancer-related and cancer-related chronic pain may also decrease gastrointestinal (GI) motility resulting in opioid-induced bowel dysfunction (OBD). Postoperative ileus has been associated with prolonged hospital stay and readmission, and thus may increase the overall hospital costs per patient with POI. Alvimopan, a peripherally acting mu-opioid receptor antagonist, accelerated time to GI recovery and reduced postoperative hospital length of stay in phase III POI clinical trials and improved symptoms of OBD compared with placebo in phase II/III clinical trials. The U.S. Food and Drug Administration is currently evaluating alvimopan for the management of POI after bowel resection. Alvimopan may provide clinically meaningful benefits to patients and may lower the economic burden of POI to the healthcare system.

  15. Signatures of sex-antagonistic selection on recombining sex chromosomes.

    PubMed

    Kirkpatrick, Mark; Guerrero, Rafael F

    2014-06-01

    Sex-antagonistic (SA) selection has major evolutionary consequences: it can drive genomic change, constrain adaptation, and maintain genetic variation for fitness. The recombining (or pseudoautosomal) regions of sex chromosomes are a promising setting in which to study SA selection because they tend to accumulate SA polymorphisms and because recombination allows us to deploy the tools of molecular evolution to locate targets of SA selection and quantify evolutionary forces. Here we use coalescent models to characterize the patterns of polymorphism expected within and divergence between recombining X and Y (or Z and W) sex chromosomes. SA selection generates peaks of divergence between X and Y that can extend substantial distances away from the targets of selection. Linkage disequilibrium between neutral sites is also inflated. We show how the pattern of divergence is altered when the SA polymorphism or the sex-determining region was recently established. We use data from the flowering plant Silene latifolia to illustrate how the strength of SA selection might be quantified using molecular data from recombining sex chromosomes.

  16. Orexin receptor antagonists as therapeutic agents for insomnia.

    PubMed

    Equihua, Ana C; De La Herrán-Arita, Alberto K; Drucker-Colin, Rene

    2013-12-25

    Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  17. Antagonistic Activity of Lactobacillus Isolates against Salmonella typhi In Vitro

    PubMed Central

    Abdel-Daim, Amira; Hassouna, Nadia; Hafez, Mohamed; Ashor, Mohamed Seif Aldeen; Aboulwafa, Mohammad M.

    2013-01-01

    Background. Enteric fever is a global health problem, and rapidly developing resistance to various drugs makes the situation more alarming. The potential use of Lactobacillus to control typhoid fever represents a promising approach, as it may exert protective actions through various mechanisms. Methods. In this study, the probiotic potential and antagonistic activities of 32 Lactobacillus isolates against Salmonella typhi were evaluated. The antimicrobial activity of cell free supernatants of Lactobacillus isolates, interference of Lactobacillus isolates with the Salmonella adherence and invasion, cytoprotective effect of Lactobacillus isolates, and possibility of concurrent use of tested Lactobacillus isolates and antibiotics were evaluated by testing their susceptibilities to antimicrobial agents, and their oxygen tolerance was also examined. Results. The results revealed that twelve Lactobacillus isolates could protect against Salmonella typhi infection through interference with both its growth and its virulence properties, such as adherence, invasion, and cytotoxicity. These Lactobacillus isolates exhibited MIC values for ciprofloxacin higher than those of Salmonella typhi and oxygen tolerance and were identified as Lactobacillus plantarum. Conclusion. The tested Lactobacillus plantarum isolates can be introduced as potential novel candidates that have to be subjected for in vivo and application studies for treatment and control of typhoid fever. PMID:24191248

  18. Duodenal ulcer perforation: the effect of H2 antagonists?

    PubMed Central

    Gillen, P.; Ryan, W.; Peel, A. L.; Devlin, H. B.

    1986-01-01

    One hundred and two patients with perforated duodenal ulcers over a 13 year period (1970 to 1982) have been prospectively followed-up at a special gastric clinic. Of the 37 patients with perforation of their acute ulcer, 34 were treated by oversew and three had an initial definitive operation (vagotomy and drainage). The remaining 65 patients presented with perforation of a chronic ulcer and 54 were treated by oversew and 11 underwent definitive surgery--nine had vagotomy and drainage and two had partial gastrectomies. Seven of the 34 patients (20.5%) with acute ulcer perforation treated by simple oversew subsequently required definitive ulcer surgery at a mean 17.5 months after perforation and 31 of the 54 patients (57.4%) with chronic ulcer perforations required definitive surgery at a mean 27.4 months after perforation. The introduction of H2 antagonists in 1977 did not alter the re-operation rate in patients with chronic ulcer perforation managed by oversew. Results of this study provide further evidence in favour of treating patients with perforation of their chronic duodenal ulcer by definitive surgery whenever possible. PMID:3789618

  19. Histamine and histamine receptor antagonists in cancer biology.

    PubMed

    Blaya, Bruno; Nicolau-Galmés, Francesca; Jangi, Shawkat M; Ortega-Martínez, Idoia; Alonso-Tejerina, Erika; Burgos-Bretones, Juan; Pérez-Yarza, Gorka; Asumendi, Aintzane; Boyano, María D

    2010-07-01

    Histamine has been demonstrated to be involved in cell proliferation, embryonic development, and tumour growth. These various biological effects are mediated through the activation of specific histamine receptors (H1, H2, H3, and H4) that differ in their tissue expression patterns and functions. Although many in vitro and in vivo studies of the modulatory roles of histamine in tumour development and metastasis have been reported, the effect of histamine in the progression of some types of tumours remains controversial; however, recent findings on the role of histamine in the immune system have shed new light on this question. This review focuses on the recent advances in understanding the roles of histamine and its receptors in tumour biology. We report our recent observations of the anti-tumoural effect of H1 histamine antagonists on experimental and human melanomas. We have found that in spite of exogenous histamine stimulated human melanoma cell proliferation, clonogenic ability and migration activity in a dose-dependent manner, the melanoma tumour growth was not modulated by in vivo histamine treatment. On the contrary, terfenadine-treatment in vitro induced melanoma cell death by apoptosis and in vivo terfenadine treatment significantly inhibited tumour growth in murine models. These observations increase our understanding of cancer biology and may inspire novel anticancer therapeutic strategies.

  20. Therapeutic potential of growth factors and their antagonists.

    PubMed Central

    Garner, A.

    1992-01-01

    This article describes studies with four peptides, epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), gastrin-releasing peptide/bombesin (GRP), and gastrin. The mitogenic and anti-secretory activities of EGF/TGF alpha appear to be mediated by a single class of high-affinity membrane receptors but may involve different signal transducing mechanisms. Biological activity of EGF resides in the N-terminal 42 amino acid fragment with the C-terminal undecapeptide determining binding affinity. A parenteral depot formulation of an EGF-related peptide or a small molecule agonist of the EGF receptor could have utility in treating various ulcerative disorders of the gut. Although antagonism of EGF (and thus TGF alpha) receptors and/or transducing mechanisms is frequently cited as a potential therapeutic approach to hyperproliferative diseases, blocking the action of TGF alpha, GRP, or gastrin with neutralizing antibodies or receptor antagonists did not influence the growth of a wide range of solid tumors in nude mice. These findings suggest that, unless tumor growth displays absolute dependency on one particular mitogen, antagonism of a specific growth factor is unlikely to have great effect in cancer therapy. PMID:1341074

  1. Can paternal leakage maintain sexually antagonistic polymorphism in the cytoplasm?

    PubMed Central

    Kuijper, B; Lane, N; Pomiankowski, A

    2015-01-01

    A growing number of studies in multicellular organisms highlight low or moderate frequencies of paternal transmission of cytoplasmic organelles, including both mitochondria and chloroplasts. It is well established that strict maternal inheritance is selectively blind to cytoplasmic elements that are deleterious to males – ’mother's curse’. But it is not known how sensitive this conclusion is to slight levels of paternal cytoplasmic leakage. We assess the scope for polymorphism when individuals bear multiple cytoplasmic alleles in the presence of paternal leakage, bottlenecks and recurrent mutation. When fitness interactions among cytoplasmic elements within an individual are additive, we find that sexually antagonistic polymorphism is restricted to cases of strong selection on males. However, when fitness interactions among cytoplasmic elements are nonlinear, much more extensive polymorphism can be supported in the cytoplasm. In particular, mitochondrial mutants that have strong beneficial fitness effects in males and weak deleterious fitness effects in females when rare (i.e. ’reverse dominance’) are strongly favoured under paternal leakage. We discuss how such epistasis could arise through preferential segregation of mitochondria in sex-specific somatic tissues. Our analysis shows how paternal leakage can dampen the evolution of deleterious male effects associated with predominant maternal inheritance of cytoplasm, potentially explaining why ’mother's curse’ is less pervasive than predicted by earlier work. PMID:25653025

  2. Applicability of DPI formulations for novel neurokinin receptor antagonist.

    PubMed

    Kumon, M; Yabe, Y; Kasuya, Y; Suzuki, M; Kusai, A; Yonemochi, E; Terada, K

    2008-05-22

    A novel triple neurokinin receptor antagonist (TNRA) could have pharmaceutical efficacy for asthma and/or chronic obstructive pulmonary disease. TNRA is potentially developed as inhalation medicine. The aim of this investigation was to evaluate the applicability of dry powder inhaler (DPI) formulation for TNRA. DPI formulation containing lactose was used for this feasibility study. Mechanofusion process for surface modification was applied on lactose particles to prepare four different DPI formulations. The mixture of TNRA and lactose was administered to rats intratracheally using an insufflator. The deposition pattern and blood concentration profile of TNRA were evaluated. Although there was no significant difference in deposition on deep lungs between the four formulations, DPI formulations containing mechanofusion-processed lactose showed longer T(max) and t(1/2) and higher AUC(0-infinity) and MRT compared to that containing intact lactose. On the other hand, the contact angle measurement showed that the mechanofusion process decreased the polar part of the surface energy of the lactose. Therefore, the prolongation of the wetting of the formulated powder mixture seemed to delay the dissolution of TNRA deposited in respiratory tract. It was concluded that DPI formulation containing mechanofusion-processed lactose could be suitable for inhalation of TNRA.

  3. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

    PubMed

    Sica, Domenic A

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

  4. An Improved Antagonist Radiotracer for the Kappa Opioid Receptor: Synthesis and Characterization of 11C-LY2459989

    PubMed Central

    Zheng, Ming-Qiang; Kim, Su Jin; Holden, Daniel; Lin, Shu-fei; Need, Anne; Rash, Karen; Barth, Vanessa; Mitch, Charles; Navarro, Antonio; Kapinos, Michael; Maloney, Kathleen; Ropchan, Jim; Carson, Richard E.; Huang, Yiyun

    2016-01-01

    The kappa opioid receptors (KOR) are implicated in a number of neuropsychiatric diseases and addictive disorders. Positron Emission Tomography (PET) with radioligands provides a means to image the KOR in vivo and investigate its function in health and disease. The purpose of this study was to develop the selective KOR antagonist 11C-LY2459989 as a PET radioligand and characterize its imaging performance in non-human primates. Methods LY2459989 was synthesized and assayed for in vitro binding to opioid receptors. Ex vivo studies in rodents were conducted to assess its potential as a tracer candidate. 11C-LY2459989 was synthesized by reaction of its iodophenyl precursor with 11C-cyanide followed by partial hydrolysis of the resulting 11C-cyanophenyl intermediate. Imaging experiments with 11C-LY2459989 were carried out in rhesus monkeys with arterial input function measurement. Imaging data were analyzed with kinetic models to derive in vivo binding parameters. Results LY2459989 is a full antagonist with high binding affinity and selectivity for KOR (Ki = 0.18, 7.68, and 91.3 nM, respectively, for κ, μ, and δ receptors). Ex vivo studies in rats indicated LY2459989 as an appropriate tracer candidate with high specific binding signals, and confirmed its KOR binding selectivity in vivo. 11C-LY2459989 was synthesized in high radiochemical purity and good specific activity. In rhesus monkeys, 11C-LY2459989 displayed a fast rate of peripheral metabolism. Similarly, 11C-LY2459989 displayed fast uptake kinetics in the brain and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, i.v.) resulted in a uniform distribution of radioactivity in the brain. Further, specific binding of 11C-LY2459989 was dose-dependently reduced by the selective KOR antagonist LY2456302 and the unlabeled LY2459989. Regional binding potential (BPND) values derived from the multilinear analysis method (MA1), as a measure of in vivo specific

  5. Identification of potential Gly/NMDA receptor antagonists by cheminformatics approach: a combination of pharmacophore modelling, virtual screening and molecular docking studies.

    PubMed

    Ugale, V G; Bari, S B

    2016-01-01

    The Gly/NMDA receptor has become known as potential target for the management of neurodegenerative diseases. Discovery of Gly/NMDA antagonists has thus attracted much attention in recent years. In the present research, a cheminformatics approach has been used to determine structural requirements for Gly/NMDA antagonism and to identify potential antagonists. Here, 37 quinoxaline derivatives were selected to develop a significant pharmacophore model with good certainty. The selected model was validated by leave-one-out cross-validation, an external test set, decoy set and Y-randomization test. Applicability domain was verified by the standardization approach. The validated 3D-QSAR model was used to screen virtual hits from the ZINC database by pharmacophore mapping. Molecular docking was used for assessment of receptor-ligand binding modes and binding affinities. The GlideScore and molecular interactions with critical amino acids were considered as crucial features to identify final hits. Furthermore, hits were analysed for in silico pharmacokinetic parameters and Lipinski's rule of five, demonstrating their potential as drug-like candidates. The PubChem and SciFinder search tools were used to authenticate the novelty of leads retrieved. Finally, five different leads have been suggested as putative novel candidates for the exploration of potent Gly/NMDA receptor antagonists.

  6. Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release.

    PubMed

    Kalinowski, Leszek; Matys, Tomasz; Chabielska, Ewa; Buczko, Włodzimierz; Malinski, Tadeusz

    2002-10-01

    This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT1)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT1-receptor antagonist-stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT1-receptor antagonists on platelet adhesion to collagen and thromboxane A2 analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 micro mol/L, which was attenuated by NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. The angiotensin II AT1-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT1-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N(G)-nitro-L-arginine methyl ester. Neither the AT2 receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A2/prostaglandin H2 receptor antagonist SQ29,548 had any effect on angiotensin II AT1-receptor antagonist-stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT1-receptor antagonists.

  7. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists

    PubMed Central

    Askling, J; Fored, C; Baecklund, E; Brandt, L; Backlin, C; Ekbom, A; Sundstrom, C; Bertilsson, L; Coster, L; Geborek, P; Jacobsson, L; Lindblad, S; Lysholm, J; Rantapaa-Dahlqvis..., S; Saxne, T; Klareskog, L; Feltelius, N

    2005-01-01

    Background: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear. Objective: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA. Methods: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53 067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed. Results: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas. Conclusion: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk. PMID:15843454

  8. Use of Enterally Delivered Angiotensin II Type Ia Receptor Antagonists to Reduce the Severity of Colitis

    PubMed Central

    Okawada, Manabu; Koga, Hiroyuki; Larsen, Scott D.; Showalter, Hollis D.; Turbiak, Anjanette J.; Jin, Xiaohong; Lucas, Peter C.; Lipka, Elke; Hillfinger, John; Kim, Jae Seung

    2011-01-01

    Background Renin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia receptor antagonists use, we hypothesized that use of angiotensin II type Ia receptor antagonists compounds which lack cell membrane permeability, and thus enteric absorption, would allow for direct enteral delivery at far higher concentrations than would be tolerated systemically, yet retain efficacy. Methods Based on the structure of the angiotensin II type Ia receptor antagonist losartan, deschloro-losartan was synthesized, which has extremely poor cell membrane permeability. Angiotensin II type Ia receptor antagonist efficacy was evaluated by determining the ability to block NF-κB activation in vitro. Dextran sodium sulfate colitis was induced in mice and angiotensin II type Ia receptor antagonist efficacy delivered transanally was assessed. Results In vitro, deschloro-losartan demonstrated near equal angiotensin II type Ia receptor blockade compared to losartan as well as another angiotensin II type Ia receptor antagonist, candesartan. In the dextran sodium sulfate model, each compound significantly improved clinical and histologic scores and epithelial cell apoptosis. Abundance of TNF-α, IL-1β, and IL6 mRNA were significantly decreased with each compound. In vitro and in vivo intestinal drug absorption, as well as measures of blood pressure and mucosal and colonic blood flow, showed significantly lower uptake of deschloro-losartan compared to losartan and candesartan. Conclusions This study demonstrated efficacy of high-dose angiotensin II type Ia receptor antagonists in this colitis model. We postulate that a specially designed angiotensin II type Ia receptor antagonist with

  9. Discovery of diarylurea P2Y(1) antagonists with improved aqueous solubility.

    PubMed

    Wang, Tammy C; Qiao, Jennifer X; Clark, Charles G; Jua, Ji; Price, Laura A; Wu, Qimin; Chang, Ming; Zheng, Joanna; Huang, Christine S; Everlof, Gerry; Schumacher, William A; Wong, Pancras C; Seiffert, Dietmar A; Stewart, Anne B; Bostwick, Jeffrey S; Crain, Earl J; Watson, Carol A; Rehfuss, Robert; Wexler, Ruth R; Lam, Patrick Y S

    2013-06-01

    Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.

  10. Conservation of receptor antagonist anti-tumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed.

    PubMed

    Ludwig, Dale L; Witte, Larry; Hicklin, Daniel J; Prewett, Marie; Bassi, Rajiv; Burtrum, Douglas; Pereira, Daniel S; Jimenez, Xenia; Fox, Floyd; Saxena, Babita; Zhou, Qinwei; Ma, Yuemei; Kang, Xiaoqiang; Patel, Dipa; Barry, Michael; Kussie, Paul; Zhu, Zhenping; Russell, Douglas A; Petersen, William L; Jury, Thomas P; Gaitan-Gaitan, Fernando; Moran, Daniel L; Delannay, Xavier; Storrs, Bradley S; Tou, Jacob; Zupec, Mark E; Gustafson, Karen S; McIntyre, John; Tarnowski, S Joseph; Bohlen, Peter

    2004-01-01

    Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.

  11. Hydrazone- and hydrazide-containing N-substituted glycines as peptoid surrogates for expedited library synthesis: application to the preparation of Tsg101-directed HIV-1 budding antagonists.

    PubMed

    Liu, Fa; Stephen, Andrew G; Adamson, Catherine S; Gousset, Karine; Aman, M Javad; Freed, Eric O; Fisher, Robert J; Burke, Terrence R

    2006-10-26

    Replacing the Pro6 in the p6(Gag)-derived 9-mer "P-E-P-T-A-P-P-E-E" with N-substituted glycine (NSG) residues is problematic. However, incorporation of hydrazone amides ("peptoid hydrazones") can be readily achieved in library fashion. Furthermore, reduction of these hydrazones to N-substituted "peptoid hydrazides" affords a facile route to library diversification. This approach is demonstrated by application to Tsg101-binding compounds designed as potential HIV budding antagonists. [reaction: see text

  12. The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists.

    PubMed

    Seely, Kathryn A; Levi, Mark S; Prather, Paul L

    2009-07-01

    The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examined whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act as ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal G-protein activity in membranes prepared from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body weight in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, trans-resveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/inverse agonists at CB1 receptors at dietary relevant concentrations. Therefore, these polyphenols and their

  13. Differences in the effects of four TRPV1 channel antagonists on lipopolysaccharide-induced cytokine production and COX-2 expression in murine macrophages.

    PubMed

    Ninomiya, Yuki; Tanuma, Sei-Ichi; Tsukimoto, Mitsutoshi

    2017-03-11

    Sepsis is a systemic inflammatory response syndrome triggered by lipopolysaccharide (LPS), an outer membrane component of gram-negative bacteria, and cytokine production via LPS-induced macrophage activation is deeply involved in its pathogenesis. Effective therapy of sepsis has not yet been established. However, it was reported that transient receptor potential vanilloid 1 (TRPV1) channel antagonist capsazepine (CPZ; a capsaicin analogue) attenuates sepsis in a murine model [Ang et al., PLoS ONE 6(9) (2011) e24535; J. Immunol. 187 (2011) 4778-4787]. Here, we profiled the effects of four TRPV1 channel antagonists, AMG9810, SB366791, BCTC and CPZ, on the release of IL-6, IL-1β and IL-18, and on expression of cyclooxygenase 2 (COX-2) in LPS-activated macrophages. Treatment of murine macrophage J774.1 cells or BALB/c mouse-derived intraperitoneal immune cells with LPS induced pro-inflammatory cytokines production and COX-2 expression. Pretreatment with AMG9810 or CPZ significantly suppressed the release of IL-6, IL-1β and IL-18, and COX-2 expression, whereas SB366791 and BCTC were less effective. These results support a role of TRPV1 channel in macrophage activation, but also indicate that only a subset of TRPV1 channel antagonists may be effective in suppressing inflammatory responses. These results suggest that at least some TRPV1 channel antagonists, such as AMG9810 and CPZ, may be candidate anti-inflammatory agents for treatment of sepsis.

  14. P2Y2 receptor antagonists as anti-allodynic agents in acute and sub-chronic trigeminal sensitization: role of satellite glial cells.

    PubMed

    Magni, Giulia; Merli, Davide; Verderio, Claudia; Abbracchio, Maria P; Ceruti, Stefania

    2015-07-01

    Trigeminal (TG) pain often lacks a satisfactory pharmacological control. A better understanding of the molecular cross-talk between TG neurons and surrounding satellite glial cells (SGCs) could help identifying innovative targets for the development of more effective analgesics. We have previously demonstrated that neuronal pro-algogenic mediators upregulate G protein-coupled nucleotide P2Y receptors (P2YRs) expressed by TG SGCs in vitro. Here, we have identified the specific P2YR subtypes involved (i.e., the ADP-sensitive P2Y1 R and the UTP-responsive P2Y2 R subtypes), and demonstrated the contribution of neuron-derived prostaglandins to their upregulation. Next, we have translated these data to an in vivo model of TG pain (namely, rats injected with Complete Freund's adjuvant in the temporomandibular joint), by demonstrating activation of SGCs and upregulation of P2Y1 R and P2Y2 R in the ipsi-lateral TG. To unequivocally link P2YRs to the development of facial allodynia, we treated animals with various purinergic antagonists. The selective P2Y2 R antagonist AR-C118925 completely inhibited SGCs activation, exerted a potent anti-allodynic effect that lasted over time, and was still effective when administration was started 6-days post induction of allodynia, i.e. under subchronic pain conditions. Conversely, the selective P2Y1 R antagonist MRS2179 was completely ineffective. Moreover, similarly to the anti-inflammatory drug acetylsalicylic acid and the known anti-migraine agent sumatriptan, the P2X/P2Y nonselective antagonist PPADS was only partially effective, and completely lost its activity under sub-chronic conditions. Taken together, our results highlight glial P2Y2 Rs as potential "druggable" targets for the successful management of TG-related pain.

  15. Development of interleukin-1 receptor antagonist mutants with enhanced antagonistic activity in vitro and improved therapeutic efficacy in collagen-induced arthritis.

    PubMed

    Dahlén, Eva; Barchan, Karin; Herrlander, Daniel; Höjman, Patrik; Karlsson, Marie; Ljung, Lill; Andersson, Mats; Bäckman, Eva; Hager, Ann-Christin Malmborg; Walse, Björn; Joosten, Leo; van den Berg, Wim

    2008-04-01

    Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of the pro-inflammatory interleukin-1-mediated activation of the interleukin-1 receptor (IL-1R). Although wild-type IL-1Ra is used for treatment of inflammatory diseases, its effect is moderate and/or short-lived. The objective of this study was to generate IL-1Ra mutants with enhanced antagonistic activity for potential therapeutic use. Using a directed evolution approach in which libraries of IL-1Ra gene mutants were generated and screened in functional assays, mutants with desired properties were identified. Initially, diversity was introduced into the IL-1Ra using random mutagenesis. Mutations resulting in enhanced antagonistic activity were identified by screening in a reporter cell assay. To further enhance the antagonistic activity, selected mutations were recombined using the DNA recombination technology Fragment-INduced Diversity (FIND). Following three rounds of FIND recombination, several mutants with up to nine times enhanced antagonistic activity (mean IC50 +/- SEM value: 0.78 +/- 0.050 vs. 6.8 +/- 1.1 ng/ml for mutant and wild-type, respectively) were identified. Sequence analysis identified the mutations D47N, E52R and E90Y as being most important for this effect, however, the mutations P38Y, H54R, Q129L and M136N further enhanced the antagonistic function. Analysis of identified mutations in protein models based on the crystal structure of the IL-1Ra/IL-1R complex suggested that mutations found to enhance the antagonistic activity had a stabilizing effect on the IL-1Ra mutants or increased the affinity for the IL-1R. Finally, the therapeutic effect of one mutant was compared to that of wild-type IL-1Ra in collagen-induced arthritis in mice. Indeed, the enhanced antagonistic effect of the mutants observed in vitro was also seen in vivo. In conclusion, these results demonstrate that directed evolution of IL-1Ra is an effective means of generating highly potent therapeutic

  16. Update on leukotriene receptor antagonists in preschool children wheezing disorders

    PubMed Central

    2012-01-01

    Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS), is the cornerstone of asthma management. Since Leukotrienes (LTs) are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs) are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy. PMID:22734451

  17. Toxic, immunostimulatory and antagonist gluten peptides in celiac disease.

    PubMed

    Silano, Marco; Vincentini, Olimpia; De Vincenzi, Massimo

    2009-01-01

    Celiac disease (CD) is an increasingly diagnosed, permanent autoimmune enteropathy, triggered, in susceptible individuals, by the ingestion of gluten, the alcohol - soluble protein fraction of some cereals, such as wheat, rye and barley. The main protein of wheat gluten is called gliadin, the similar proteins of rye and barley are secalin and hordein, respectively. Approximately 96% of CD patients express the HLA molecule DQ2, while the remainder mostly express the less common haplotype DQ8, reflecting the pivotal role of these molecules in the pathogenesis of CD. Because of their aminoacid sequence and tri-dimensional structure, gluten peptides selectively bind to these HLA alleles present on the surface of antigen presenting cells and then they are presented to the T lymphocytes in intestinal mucosa, thus starting the inflammatory immune response. CD is defined by the characteristic histological changes of small bowel mucosa: villous atrophy, crypts hyperplasia and T cells infiltration of the lamina propria, along with the increase of the number of intra-epithelial lymphocytes. The withdrawal of the gluten- containing food from the diet determines a complete recovery of the intestinal mucosa, whereas the reintroduction causes a relapse of the disease. This review focuses on the description of gluten peptides that elicit the mucosal immune response via the activation of innate and adaptive immunity in CD. It also describes the antagonist gluten peptides, obtained by artificial modification of gluten T epitopes or naturally occurring in the alcohol protein fraction of a cultivar of durum wheat, able to immuno-modulate the pathogenic immune response of CD.

  18. Selective β2-adrenergic Antagonist Butoxamine Reduces Orthodontic Tooth Movement

    PubMed Central

    Sato, T.; Miyazawa, K.; Suzuki, Y.; Mizutani, Y.; Uchibori, S.; Asaoka, R.; Arai, M.; Togari, A.; Goto, S.

    2014-01-01

    Recently, involvement of the sympathetic nervous system in bone metabolism has attracted attention. β2-Adrenergic receptor (β2-AR) is presented on osteoblastic and osteoclastic cells. We previously demonstrated that β-AR blockers at low dose improve osteoporosis with hyperactivity of the sympathetic nervous system via β2-AR blocking, while they may have a somewhat inhibitory effect on osteoblastic activity at high doses. In this study, the effects of butoxamine (BUT), a specific β2-AR antagonist, on tooth movement were examined in spontaneously hypertensive rats (SHR) showing osteoporosis with hyperactivity of the sympathetic nervous system. We administered BUT (1 mg/kg) orally, and closed-coil springs were inserted into the upper-left first molar. After sacrifice, we calculated the amount of tooth movement and analyzed the trabecular microarchitecture and histomorphometry. The distance in the SHR control was greater than that in the Wistar-Kyoto rat group, but no significant difference was found in the SHR treated with BUT compared with the Wistar-Kyoto rat control. Analysis of bone volume per tissue volume, trabecular number, and osteoclast surface per bone surface in the alveolar bone showed clear bone loss by an increase of bone resorption in SHR. In addition, BUT treatment resulted in a recovery of alveolar bone loss. Furthermore, TH-immunoreactive nerves in the periodontal ligament were increased by tooth movement, and BUT administration decreased TH-immunoreactive nerves. These results suggest that BUT prevents alveolar bone loss and orthodontic tooth movement via β2-AR blocking. PMID:24868013

  19. Antagonistic interaction between Trichoderma asperellum and Phytophthora capsici in vitro*

    PubMed Central

    Jiang, Heng; Zhang, Liang; Zhang, Jing-ze; Ojaghian, Mohammad Reza; Hyde, Kevin D.

    2016-01-01

    Phytophthora capsici is a phytopathogen that causes a destructive pepper blight that is extremely difficult to control. Using a fungicide application against the disease is costly and relatively ineffective and there is also a huge environmental concern about the use of such chemicals. The genus Trichoderma has been known to have a potential biocontrol issue. In this paper we investigate the mechanism for causing the infection of T. asperellum against P. capsici. Trichoderma sp. (isolate CGMCC 6422) was developed to have a strong antagonistic action against hyphae of P. capsici through screening tests. The strain was identified as T. asperellum through using a combination of morphological characteristics and molecular data. T. asperellum was able to collapse the mycelium of the colonies of the pathogen through dual culture tests by breaking down the pathogenic hyphae into fragments. The scanning electron microscope showed that the hyphae of T. asperellum surrounded and penetrated the pathogens hyphae, resulting in hyphal collapse. The results show that seven days after inoculation, the hyphae of the pathogen were completely degraded in a dual culture. T. asperellum was also able to enter the P. capsici oospores through using oogonia and then developed hyphae and produced conidia, leading to the disintegration of the oogonia and oospores. Seven days after inoculation, an average 10.8% of the oospores were infected, but at this stage, the structures of oospores were still intact. Subsequently, the number of infected oospores increased and the oospores started to collapse. Forty-two days after inoculation, almost all the oospores were infected, with 9.3% of the structures of the oospores being intact and 90.7% of the oospores having collapsed.

  20. Selective β2-adrenergic Antagonist Butoxamine Reduces Orthodontic Tooth Movement.

    PubMed

    Sato, T; Miyazawa, K; Suzuki, Y; Mizutani, Y; Uchibori, S; Asaoka, R; Arai, M; Togari, A; Goto, S

    2014-08-01

    Recently, involvement of the sympathetic nervous system in bone metabolism has attracted attention. β2-Adrenergic receptor (β2-AR) is presented on osteoblastic and osteoclastic cells. We previously demonstrated that β-AR blockers at low dose improve osteoporosis with hyperactivity of the sympathetic nervous system via β2-AR blocking, while they may have a somewhat inhibitory effect on osteoblastic activity at high doses. In this study, the effects of butoxamine (BUT), a specific β2-AR antagonist, on tooth movement were examined in spontaneously hypertensive rats (SHR) showing osteoporosis with hyperactivity of the sympathetic nervous system. We administered BUT (1 mg/kg) orally, and closed-coil springs were inserted into the upper-left first molar. After sacrifice, we calculated the amount of tooth movement and analyzed the trabecular microarchitecture and histomorphometry. The distance in the SHR control was greater than that in the Wistar-Kyoto rat group, but no significant difference was found in the SHR treated with BUT compared with the Wistar-Kyoto rat control. Analysis of bone volume per tissue volume, trabecular number, and osteoclast surface per bone surface in the alveolar bone showed clear bone loss by an increase of bone resorption in SHR. In addition, BUT treatment resulted in a recovery of alveolar bone loss. Furthermore, TH-immunoreactive nerves in the periodontal ligament were increased by tooth movement, and BUT administration decreased TH-immunoreactive nerves. These results suggest that BUT prevents alveolar bone loss and orthodontic tooth movement via β2-AR blocking.