Sample records for competitive receptor antagonist

  1. Quinoxalinediones: Potent Competitive Non-NMDA Glutamate Receptor Antagonists

    Microsoft Academic Search

    Tage Honore; Steve N. Davies; Jorgen Drejer; Elizabeth J. Fletcher; Poul Jacobsen; David Lodge; Flemming E. Nielsen

    1988-01-01

    The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the ``non-NMDA'' glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of

  2. The AMPA receptor antagonist GYKI 52466 reverses the anti-cataleptic effects of the competitive NMDA receptor antagonist CGP 37849

    Microsoft Academic Search

    Wolfgang Hauber; Marc T. Waldenmeier

    1994-01-01

    The effects of the AMPA receptor antagonist GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo- diazepine HCI) on haloperidol-induced catalepsy were tested in drug-naive rats and in rats pretreated with the competitive NMDA receptor antagonist CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid). CGP 37849 (4 mg\\/kg i.p.) given alone significantly reversed haloperidol-induced catalepsy (0.5 mg\\/kg i.p.) while GYKI 52466 (4.8 mg\\/kg i.p.) given alone was without effect. Administration

  3. Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors

    Microsoft Academic Search

    Hugo Rubén Arias

    2000-01-01

    Identification of all residues involved in the recognition and binding of cholinergic ligands (e.g. agonists, competitive antagonists, and noncompetitive agonists) is a primary objective to understand which structural components are related to the physiological function of the nicotinic acetylcholine receptor (AChR). The picture for the localization of the agonist\\/competitive antagonist binding sites is now clearer in the light of newer

  4. Synergy between Pairs of Competitive Antagonists at Adult Human Muscle Acetylcholine Receptors

    PubMed Central

    Liu, Man; Dilger, James P.

    2008-01-01

    Background Synergistic neuromuscular blocking effects have been observed clinically with certain pairs of nicotinic acetylcholine receptor (nAChR) competitive antagonists. The mechanism for synergy has not been elucidated. We tested the hypothesis that synergy arises from a differential selectivity of antagonists for the two ligand binding sites on adult human nAChR. Methods We expressed nAChR in BOSC23 cells. We applied ACh with or without antagonists to outside-out patches and measured macroscopic currents at room temperature. We determined the IC90 for (+)-tubocurarine, metocurine, pancuronium, vecuronium, cisatracurium, rocuronium, and atracurium. For 15 combinations of two antagonists, we determined the IC90 for one antagonist in the presence of the IC70 of a second antagonist. We constructed isobolograms for 90% inhibition. For single antagonists, we measured inhibition of receptors containing mutations in the ?- and ?-subunits to determine site selectivity. Results Two pairs of antagonists, metocurine+cisatracurium and cisatracurium+atracurium exhibited additive inhibition. Ten combinations, including (+)-tubocurarine+pancuronium and pancuronium+vecuronium, were highly synergistic such that the combination was 2?3 times more effective than expected for additivity. Three combinations were 1.5?1.6 times more effective than expected for additivity. Inhibition by (+)-tubocurarine and metocurine was sensitive to mutations in the ?-subunit only. Vecuronium was affected by the ?-subunit mutation only. Inhibition by other antagonists was decreased by mutations in either subunit. Conclusions Many combinations of antagonists exhibited synergistic effects on adult human nAChR. Synergy was observed with structurally similar as well as dissimilar antagonists. The degree of synergy did not always correlate well with site specificity assayed with mutants. In some, but not all cases, the synergy at the receptor level correlated with clinical determinations of synergy. We conclude that the synergistic actions of muscle relaxants can be partially explained by direct interactions with adult human nAChR. PMID:18633030

  5. Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes.

    PubMed Central

    Eglen, R. M.; Whiting, R. L.

    1987-01-01

    The affinity of a number of 'selective' agonists and antagonists has been assessed at atrial or ileal muscarinic receptors by use of in vitro functional analysis. The most selective compound for ileal muscarinic receptors was silabenzhexol (approx. 50 fold), and to a lesser extent benzhexol (approx. 5 fold). Conversely, the most selective compound for the atrial muscarinic receptors was AF-DX 116 (approx. 6 fold). The novel M1-receptor antagonist, telenzepine and other antagonists such as propantheline and isopropamide did not distinguish between atrial and ileal receptors. Dicyclomine, adiphenine, hexahydroadiphenine and oxyphenonium exhibited competitive antagonism at atrial receptors but non-competitive antagonism at ileal receptors. No conclusions could, therefore, be drawn with regard to their selectivity. The agonists, arecaidine propargyl ester (APE), ethoxyethyltriethylammonium (EOE) and carbachol, exhibited some selectivity in potency but little difference in affinity. It is concluded that the study supports the existence of ileal and atrial muscarinic receptor subtypes. However, the use of dicyclomine and related compounds in receptor classification is limited. PMID:3580704

  6. Competitive as well as uncompetitive N-methyl-D-aspartate receptor antagonists affect cortical neuronal morphology and cerebral glucose metabolism

    Microsoft Academic Search

    Richard J. Hargreaves; Michael Rigby; David Smith; Raymond G. Hill; Leslie L. Iversen

    1993-01-01

    The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849

  7. Competitive molecular docking approach for predicting estrogen receptor subtype ? agonists and antagonists

    PubMed Central

    2014-01-01

    Background Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with the endocrine system of vertebrates, often through direct or indirect interactions with nuclear receptor proteins. Estrogen receptors (ERs) are particularly important protein targets and many EDCs are ER binders, capable of altering normal homeostatic transcription and signaling pathways. An estrogenic xenobiotic can bind ER as either an agonist or antagonist to increase or inhibit transcription, respectively. The receptor conformations in the complexes of ER bound with agonists and antagonists are different and dependent on interactions with co-regulator proteins that vary across tissue type. Assessment of chemical endocrine disruption potential depends not only on binding affinity to ERs, but also on changes that may alter the receptor conformation and its ability to subsequently bind DNA response elements and initiate transcription. Using both agonist and antagonist conformations of the ER?, we developed an in silico approach that can be used to differentiate agonist versus antagonist status of potential binders. Methods The approach combined separate molecular docking models for ER agonist and antagonist conformations. The ability of this approach to differentiate agonists and antagonists was first evaluated using true agonists and antagonists extracted from the crystal structures available in the protein data bank (PDB), and then further validated using a larger set of ligands from the literature. The usefulness of the approach was demonstrated with enrichment analysis in data sets with a large number of decoy ligands. Results The performance of individual agonist and antagonist docking models was found comparable to similar models in the literature. When combined in a competitive docking approach, they provided the ability to discriminate agonists from antagonists with good accuracy, as well as the ability to efficiently select true agonists and antagonists from decoys during enrichment analysis. Conclusion This approach enables evaluation of potential ER biological function changes caused by chemicals bound to the receptor which, in turn, allows the assessment of a chemical's endocrine disrupting potential. The approach can be used not only by regulatory authorities to perform risk assessments on potential EDCs but also by the industry in drug discovery projects to screen for potential agonists and antagonists. PMID:25349983

  8. Roles of Amino Acids and Subunits in Determining the Inhibition of Nicotinic Acetylcholine Receptors by Competitive Antagonists

    PubMed Central

    Dilger, James P.; Vidal, Ana Maria; Liu, Man; Mettewie, Claire; Suzuki, Takahiro; Pham, Anh; Demazumder, Deeptankar

    2008-01-01

    Background Binding sites for agonists and competitive antagonists (nondepolarizing neuromuscular blocking agents) are located at the ?–? and ?–? subunit interfaces of adult nicotinic acetylcholine receptors. Most information about the amino acids that participate in antagonist binding comes from binding studies with (+)-tubocurarine and metocurine. These bind selectively to the ?–? interface but are differentially sensitive to mutations. To test the generality of this observation, the authors measured current inhibition by five competitive antagonists on wild-type and mutant acetylcholine receptors. Methods HEK293 cells were transfected with wild-type or mutant (?Y198F, ?D59A, ?D59N, ?D173A, ?D173N, ?D180K) mouse muscle acetylcholine receptor complementary DNA. Outside-out patches were excised and perfused with acetylcho-line in the absence and presence of antagonist. Concentration–response curves were constructed to determine antagonist IC50. An antagonist-removal protocol was used to determine dissociation and association rates. Results Effects of mutations were antagonist specific. ?Y198F decreased the IC50 of (+)-tubocurarine 10-fold, increased the IC50 of vecuronium 5-fold, and had smaller effects on other antagonists. (+)-Tubocurarine was the most sensitive antagonist to ?D173 mutations. ?D59 mutations had large effects on metocurine and cisatracurium. ?D180K decreased inhibition by pancuronium, vecuronium, and cisatracurium. Inhibition by these antagonists was increased for receptors containing two ? subunits but no ? subunit. Differences in IC50 arose from differences in both dissociation and association rates. Conclusion Competitive antagonists exhibited different patterns of sensitivity to mutations. Except for pancuronium, the antagonists were sensitive to mutations at the ?–? interface. Pancuronium, vecuronium, and cisatracurium were selective for the ?–? interface. This suggests the possibility of synergistic inhibition by pairs of antagonists. PMID:17525594

  9. GABAA receptor open-state conformation determines non-competitive antagonist binding

    PubMed Central

    Chen, Ligong; Xue, Ling; Giacomini, Kathleen M.; Casida, John E.

    2010-01-01

    The ?-aminobutyric acid (GABA) type A receptor (GABAAR) is one of the most important targets for insecticide action. The human recombinant ?3 homomer is the best available model for this binding site and 4-n-[3H]propyl-4’-ethynylbicycloorthobenzoate ([3H]EBOB) is the preferred non-competitive antagonist (NCA) radioligand. The uniquely high sensitivity of the ?3 homomer relative to the much-less-active but structurally-very-similar ?1 homomer provides an ideal comparison to elucidate structural and functional features important for NCA binding. The ?1 and ?3 subunits were compared using chimeragenesis and mutagenesis and various combinations with the ?1 subunit and modulators. Chimera ?3/?1 with the ?3 subunit extracellular domain and the ?1 subunit transmembrane helices retained the high [3H]EBOB binding level of the ?3 homomer while chimera ?1/?3 with the ?1 subunit extracellular domain and the ?3 subunit transmembrane helices had low binding activity similar to the ?1 homomer. GABA at 3 µM stimulated heteromers ?1?1 and ?1?3 binding levels more than 2-fold by increasing the open probability of the channel. Addition of the ?1 subunit rescued the inactive ?1/?3 chimera close to wildtype ?1?1 activity. EBOB binding was significantly altered by mutations ?1S15’N and ?3N15’S compared with wildtype ?1 and ?3, respectively. However, the binding activity of ?1?1S15’N was insensitive to GABA and ?1?3N15’S was stimulated much less than wildtype ?1?3 by GABA. The inhibitory effect of etomidate on NCA binding was reduced more than 5-fold by the mutation ?3N15’S. Therefore, the NCA binding site is tightly regulated by the open-state conformation that largely determines GABAA receptor sensitivity. PMID:21111751

  10. Molecular modeling of human pentameric alpha(7) neuronal nicotinic acetylcholine receptor and its interaction with its agonist and competitive antagonist.

    PubMed

    Parthiban, Marimuthu; Rajasekaran, Mohan Babu; Ramakumar, Suryanarayanarao; Shanmughavel, Piramanayagam

    2009-04-01

    The nicotinic Acetylcholine Receptor (nAChR) is the major class of neurotransmitter receptors that is involved in many neurodegenerative conditions such as schizophrenia, Alzheimer's and Parkinson's diseases. The N-terminal region or Ligand Binding Domain (LBD) of nAChR is located at pre- and post-synaptic nervous system, which mediates synaptic transmission. nAChR acts as the drug target for agonist and competitive antagonist molecules that modulate signal transmission at the nerve terminals. Based on Acetylcholine Binding Protein (AChBP) from Lymnea stagnalis as the structural template, the homology modeling approach was carried out to build three dimensional model of the N-terminal region of human alpha(7)nAChR. This theoretical model is an assembly of five alpha(7) subunits with 5 fold axis symmetry, constituting a channel, with the binding pocket present at the interface region of the subunits. alpha-neurotoxin is a potent nAChR competitive antagonist that readily blocks the channel resulting in paralysis. The molecular interaction of alpha-Bungarotoxin, a long chain alpha-neurotoxin from (Bungarus multicinctus) and human alpha(7)nAChR was studied. Agonists such as acetylcholine, nicotine, which are used in a diverse array of biological activities, such as enhancements of cognitive performances, were also docked with the theoretical model of human alpha(7)nAChR. These docked complexes were analyzed further for identifying the crucial residues involved in interaction. These results provide the details of interaction of agonists and competitive antagonists with three dimensional model of the N-terminal region of human alpha(7)nAChR and thereby point to the design of novel lead compounds. PMID:19236104

  11. Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle

    Microsoft Academic Search

    P. M. B. Cahusac; S. C. MAVULATIb

    2009-01-01

    Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-?]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC50 of 8.7 ?M

  12. Effects of competitive and noncompetitive antagonists of the N-methyl-D-aspartate receptor on the analgesic action of delta 1- and delta 2-opioid receptor agonists in mice.

    PubMed Central

    Bharagava, H. N.; Zhao, G. M.

    1996-01-01

    1. The effects of MK-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and LY 235959, a competitive antagonists of the NMDA receptor on the analgesic actions of [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2, Glu4] deltorphin II (deltorphin II), the putative delta 1- and delta 2-opioid receptor agonists, respectively, were determined in the male Swiss-Webster mice. 2. Intracerebroventricular administration of DPDPE or deltorphin II produced analgesia. MK-801 administered intraperitoneally 10 min before the injection of DPDPE or deltorphin II, dose-dependently antagonized the analgesic actions of both drugs. 3. LY 235959 also dose-dependently antagonized the analgesic actions of DPDPE and deltorphin II. 4. The effects of MK-801 and LY 235959 on the binding of [3H]-DPDPE to mouse brain membranes were also determined. Neither of the NMDA receptor antagonists had any effect on the binding of [3H]-DPDPE. 5. It is concluded that competitive and noncompetitive antagonists of the NMDA receptor antagonize the analgesic action of delta 1- and delta 2-opioid receptor agonists and that such effects are not mediated via a direct interaction with brain delta-opioid receptors. PMID:8982505

  13. Research report R egion-specific changes in NMDA receptor mRNA induced by chronic morphine treatment are prevented by the co-administration of the competitive NMDA receptor antagonist LY274614

    Microsoft Academic Search

    Hongbo Zhu; Marina Brodsky; A. Laurel Gorman; Charles E. Inturrisi

    The steady-state mRNA levels of the NMDA receptor NR1 subunit were determined by a quantitative solution hybridization assay in selected CNS regions associated with antinociception in the rat. Tissues were obtained by microdissection from rats treated chronically with morphine alone or in combination with LY274614, a competitive NMDA receptor antagonist. Morphine treatment for 7 days resulted in the development of

  14. Xanthines as Adenosine Receptor Antagonists

    Microsoft Academic Search

    Christa E. Müller; Kenneth A. Jacobson

    \\u000a The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the\\u000a literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogues were subsequently\\u000a synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of\\u000a the four AR subtypes.

  15. 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.

  16. Tachykinin NK 1 Receptor Antagonists

    Microsoft Academic Search

    R. Patacchini; C. A. Maggi

    \\u000a This chapter is focused on the pharmacology of most relevant tachykinin NK1 receptor-selective compounds, with emphasis on the progress ofknowledge made possible by their use and on the therapeutic\\u000a perspectives of these drugs. The first peptide antagonists of SP, synthesized about 20 years ago, were hampered by poor selectivity\\u000a for NK1 receptors and other serious side effects. Since then the

  17. The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors

    SciTech Connect

    Grandi?, Marjana [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia); Aráoz, Romulo; Molgó, Jordi [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Turk, Tom; Sep?i?, Kristina [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia)] [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia); Benoit, Evelyne [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Frangež, Robert, E-mail: robert.frangez@vf.uni-lj.si [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)

    2012-12-01

    APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve–hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC{sub 50} = 0.74 ?M), without affecting directly-elicited twitch tension up to 2.72 ?M. The compound (0.007–3.40 ?M) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 ?M, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC{sub 50} = 0.36 ?M) without significant change in the resting membrane potential of the muscle fibers up to 3.40 ?M. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (?1{sub 2}?1??) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 ?M), indicating a higher affinity of the compound for Torpedo (?1{sub 2}?1??) than for the mouse (?1{sub 2}?1??) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. -- Highlights: ? APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ? APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.

  18. Neurokinin-3 receptor-specific antagonists talnetant and osanetant show distinct mode of action in cellular Ca2+ mobilization but display similar binding kinetics and identical mechanism of binding in ligand cross-competition.

    PubMed

    Tian, Gaochao; Wilkins, Dee; Scott, Clay W

    2007-03-01

    Talnetant and osanetant, two structurally diverse antagonists of neurokinin-3 receptor (NK3), displayed distinct modes of action in Ca2+ mobilization. Although talnetant showed a normal Schild plot with a slope close to unity and a Kb similar to its Ki value in binding, osanetant presented an aberrant Schild with a steep slope (3.3 +/- 0.5) and a Kb value (12 nM) significantly elevated compared with its Ki value (0.8 nM) in binding. Kinetic binding experiments indicated a simple one-step binding mechanism with relatively fast on- and off-rates for both antagonists, arguing against slow onset of antagonism as the reason for abnormal Schild. This conclusion was supported by prolonged preincubation of antagonist that failed to improve the observed aberrant Schild. In ligand cross-competition binding, both talnetant and osanetant displayed linear reciprocal plots of identical slope when [MePhe7]neurokinin B (NKB) was used as the other competition partner with 125I-[MePhe7]NKB as the radioligand, indicating competitive binding of either antagonist with regard to [MePhe7]NKB. Similar patterns were obtained when talnetant was tested against osanetant, indicating competitive binding between the two antagonists as well. These results were reproduced when [3H]4-quinolinecarboxamide (SB222200), a close derivative of talnetant, was used as the radioligand. Taken together, these data strongly suggest binding of both talnetant and osanetant at the orthosteric binding site with similar kinetic properties and do not support the hypothesis that the aberrant Schild observed in functional assays for osanetant is derived from differences in the mechanism of binding for these NK3 antagonists. PMID:17172464

  19. Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

    E-print Network

    Hubin, Tim

    Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists Gina C. Valks, Graeme Mc configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been,4,8,11-tetraazacyclotetradecane)), Figure 1c, is a drug that interacts with a cell surface protein (CXCR4) via hydrogen bonding

  20. Tricyclic aminopyrimidine histamine H 4 receptor antagonists

    Microsoft Academic Search

    Brad M. Savall; Laurent Gomez; Frank Chavez; Michael Curtis; Steven P. Meduna; Aaron Kearney; Paul Dunford; Jeffery Cowden; Robin L. Thurmond; Cheryl Grice; James P. Edwards

    2011-01-01

    This report discloses the development of a series of tricyclic histamine H4 receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H4 receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.

  1. Morphine-induced catalepsy is augmented by NMDA receptor antagonists, but is partially attenuated by an AMPA receptor antagonist

    Microsoft Academic Search

    Thomas M. Tzschentke; Werner J. Schmidt

    1996-01-01

    High doses of morphine produce a state of behavioural inactivity and muscular rigidity. This type of ‘catalepsy’ is clearly different from the state which is produced by the administration of neuroleptics, e.g. haloperidol. While haloperidol-induced catalepsy can easily be antagonised by NMDA receptor antagonists, there has been a report that the non-competitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) potentiates morphine-induced catalepsy.

  2. Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

    SciTech Connect

    Fujii, Yasuyuki, E-mail: y.fujii@po.rd.taisho.co.jp [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan)] [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan)] [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Igarashi, Yasuyuki [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan)] [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan); Goitsuka, Ryo [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)] [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

  3. 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

  4. Bradykinin receptors and their antagonists

    Microsoft Academic Search

    Domenico Regoli; Suzanne Nsa Allogho; Anna Rizzi; Fernand Junior Gobeil

    1998-01-01

    Bradykinin and related kinins act on two receptor types, named B1 and B2. Initially identified in classical bioassays, these receptors have been cloned and characterized in binding assays performed on plasma membranes of cells expressing the native or the transfected human kinin B1 or B2 receptor types. The two classification criteria recommended by Schild, namely the order of potency of

  5. 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. PMID:25707577

  6. Effect of nonselective and selective opioid receptors antagonists on antinociceptive action of acetaminophen [part III].

    PubMed

    Bujalska, M

    2004-01-01

    The influence of naloxone (NAL), a competitive antagonist of mu, kappa, delta and sigma receptors; D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP), selective antagonist of mu-opioid receptors; nor-binaltorphimine (NOR-BNI), a potent and higly selective kappa opioid receptor antagonist; naltrindole (NTI), a delta-opioid receptor antagonist and naltriben (NTB), a highly selective delta(2)-opioid receptor antagonist on antinociceptive action of acetaminophen (ACETA) was studied in rats. NAL administered intraperitoneally (ip) or intracerebroventricularly (icv), and CTOP and NOR-BNI administered icv, markedly decreased the antinociceptive activity of the high dose of ACETA (400 mg/kg). Pretreatment with NTI (sc), as well as with naloxone (it), and NTB (it) slightly but significantly attenuated the ACETA antinociception. The possible involvement of the opioidergic systems in antinociceptive activity of ACETA is discussed. PMID:15591641

  7. Overview of receptor interactions of agonists and antagonists.

    PubMed

    Kenakin, Terry

    2008-09-01

    Historically, the earliest methods used to quantitatively measure the fundamental properties of drugs (namely affinity and efficacy) employed isolated tissues, and it is in this realm that the null methods used to define "receptor pharmacology" were described. This unit describes these methods and their use to specifically classify agonists (through potency ratios and determination of relative affinities and efficacies) and antagonists (through analysis of surmountable and insurmountable antagonism) to yield estimates of potency. Different drugs can yield different behaviors in various tissues, so this unit is centered on a flow diagram to indicate the type of analysis appropriate for the behavior observed. For example, some agonists may be full agonists in some tissues and partial agonists in others, while some antagonists may demonstrate surmountable simple competitive antagonism in some tissues and insurmountable non-competitive antagonism in others. Methods exist for determination of affinity and efficacy for all of these behaviors, and these are delineated in this unit. PMID:22294222

  8. 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

  9. Antagonistic interactions between plant competition and insect herbivory.

    PubMed

    Schädler, Martin; Brandl, Roland; Haase, Josephine

    2007-06-01

    Interspecific competition between plants and herbivory by specialized insects can have synergistic effects on the growth and performance of the attacked host plant. We tested the hypothesis that competition between plants may also negatively affect the performance of herbivores as well as their top-down effect on the host plant. In such a case, the combined effects of competition and herbivory may be less than expected from a simple multiplicative response. In other words, competition and herbivory may interact antagonistically. In a greenhouse experiment, Poa annua was grown in the presence or absence of a competitor (either Plantago lanceolata or Trifolium repens), as well as with or without a Poa-specialist aphid herbivore. Both competition and herbivory negatively affected Poa growth. Competition also reduced aphid density on Poa. This effect could in part be explained by changes in the biomass and the nitrogen content of Poa shoots. In treatments with competitors, reduced aphid densities alleviated the negative effect of herbivory on above- and belowground Poa biomass. Hence, we were able to demonstrate an antagonistic interaction between plant-plant interspecific competition and herbivory. However, response indices suggested that antagonistic interactions between competition and herbivory were contingent on the identity of the competitor. We found the antagonistic effect only in treatments with T. repens as the competitor. We conclude that both competitor identity and the herbivore's ability to respond with changes in its density or activity to plant competition affect the magnitude and direction (synergistic vs. antagonistic) of the interaction between competition and herbivory on plant growth. PMID:17601141

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

    SciTech Connect

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China) [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States)] [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)] [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China) [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China) [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    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.

  11. Tachykinin receptors antagonists: from research to clinic.

    PubMed

    Quartara, Laura; Altamura, Maria

    2006-08-01

    In this chapter it is described how, starting from different approaches and through extensive medicinal chemistry studies, several discovery compounds were optimized and reached the development stage. The first tachykinin receptor antagonist to reach the market in 2003 for chemotherapy-induced emesis has been aprepitant. Other clinical candidates (for central nervous system disorders: osanetant, talnetant and saredutant; for irritable bowel syndrome: nepadutant and saredutant) are in advanced clinical phase. The clinical studies reported in the literature and the destiny of the clinical candidates, where available, will be reviewed. PMID:16918326

  12. Phenylacetamides as selective ?-1A adrenergic receptor antagonists

    Microsoft Academic Search

    Michael A. Patane; Robert M. DiPardo; Randall C. Newton; RoseAnn P. Price; Theodore P. Broten; Raymond S. L. Chang; Richard W. Ransom; Jerry Di Salvo; Dhanapalan Nagarathnam; Carlos Forray; Charles Gluchowski; Mark G. Bock

    2000-01-01

    A novel class of potent and selective ?-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known ?-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies

  13. Snake neurotoxin ?-bungarotoxin is an antagonist at native GABAA receptors

    PubMed Central

    Hannan, Saad; Mortensen, Martin; Smart, Trevor G.

    2015-01-01

    The snake neurotoxin ?-bungarotoxin (?-Bgtx) is a competitive antagonist at nicotinic acetylcholine receptors (nAChRs) and is widely used to study their function and cell-surface expression. Increasingly, ?-Bgtx is also used as an imaging tool for fluorophore-labelling studies, and given the structural conservation within the pentameric ligand-gated ion channel family, we assessed whether ?-Bgtx could bind to recombinant and native ?-aminobutyric type-A receptors (GABAARs). Applying fluorophore-linked ?-Bgtx to recombinant ?x?1/2?2 GABAARs expressed in HEK-293 cells enabled clear cell-surface labelling of ?2?1/2?2 contrasting with the weaker staining of ?1/4?1/2?2, and no labelling for ?3/5/6?1/2?2. The labelling of ?2?2?2 was abolished by bicuculline, a competitive antagonist at GABAARs, and by d-tubocurarine (d-Tc), which acts in a similar manner at nAChRs and GABAARs. Labelling by ?-Bgtx was also reduced by GABA, suggesting that the GABA binding site at the receptor ?–? subunit interface forms part of the ?-Bgtx binding site. Using whole-cell recording, high concentrations of ?-Bgtx (20 ?M) inhibited GABA-activated currents at all ?x?2?2 receptors examined, but at lower concentrations (5 ?M), ?-Bgtx was selective for ?2?2?2. Using ?-Bgtx, at low concentrations, permitted the selective inhibition of ?2 subunit-containing GABAARs in hippocampal dentate gyrus granule cells, reducing synaptic current amplitudes without affecting the GABA-mediated tonic current. In conclusion, ?-Bgtx can act as an inhibitor at recombinant and native GABAARs and may be used as a selective tool to inhibit phasic but not tonic currents in the hippocampus. PMID:25634239

  14. Quantitative structure activity relationship (QSAR) of competitive N-methyl-D-aspartate (NMDA) antagonists

    NASA Astrophysics Data System (ADS)

    Korkut, Anil; Varnali, Tereza

    Glutamic acid is an excitatory amino acid neurotransmitter in the mammalian central nervous system and the NMDA molecule binds to NMDA-type glutamic acid receptors as a glutamic acid analogue, in vitro. The NMDA-type glutamic acid receptors are known for their function in many neural processes, such as neural plasticity, learning and memory. In addition, excessive NMDA receptor activity has been shown to be related to neurodegenerative diseases like epilepsy so the design of new NMDA antagonists has extra importance as potent drugs for various neural diseases. Potential antagonist molecules are usually synthesized and their activity is measured by experimental techniques. Here, computational chemistry methods are applied to develop a model, which allows one to predict the activity of potent competitive NMDA antagonists. First, various molecular parameters are calculated for a series of competitive NMDA antagonists with known activity values and those parameters are used to make a regression analysis which provides a model that relates the computationally calculated parameters to experimentally determined activity values. By the quantitative structure activity relationship (QSAR) model developed here, it is possible to predict the activity of a potent drug before its synthesis since only theoretically determined molecular parameters are used for the prediction.

  15. Potent bradykinin B 1 receptor antagonists: 4-Substituted phenyl cyclohexanes

    Microsoft Academic Search

    Dai-Shi Su; John L. Lim; M. Kristine Markowitz; Bang-Lin Wan; Kathy L. Murphy; Duane R. Reiss; C. Meacham Harrell; Stacy S. O’Malley; Rick W. Ransom; Raymond S. L. Chang; Douglas J. Pettibone; Cuyue Tang; Thomayant Prueksaritanont; Roger M. Freidinger; Mark G. Bock

    2007-01-01

    Selective bradykinin (BK) B1 receptor antagonists have been shown to be antinociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure–activity relationships of the biphenyl moiety of the lead compound 1 provided a potent new structural class of BK B1 receptor antagonists.

  16. Antagonists at the neurokinin receptors--recent patent literature.

    PubMed

    Giardina, Giuseppe A M; Gagliardi, Stefania; Martinelli, Marisa

    2003-08-01

    This review describes the patent applications and relevant scientific literature published during 2002 in the field of novel neurokinin receptor antagonists, with an emphasis on the medicinal chemistry of recent patent publications. A brief update on the development status of compounds including: the neurokinin-1 receptor antagonists aprepitant (Merck & Co Inc), vofopitant, ezlopitant (Pfizer Inc), R-673 (F Hoffmann-La Roche Ltd); the neurokinin-2 receptor antagonists nepadutant (Menarini Ricerche SpA), saredutant (Sanofi-Synthelabo), SR-144190 (Sanofi-Synthelabo) and UK-290795 (Pfizer Inc); and the neurokinin-3 receptor antagonists osanetant (Sanofi-Synthelabo) and talnetant (GlaxoSmithKline plc) will be given. The review also reports the recent published patent literature in the area of novel therapeutic uses and novel formulations and combinations claimed for neurokinin receptor antagonists. PMID:12917772

  17. Aldosterone receptor antagonists: current perspectives and therapies

    PubMed Central

    Guichard, Jason L; Clark, Donald; Calhoun, David A; Ahmed, Mustafa I

    2013-01-01

    Aldosterone is a downstream effector of angiotensin II in the renin–angiotensin–aldosterone system and binds to the mineralocorticoid receptor. The classical view of aldosterone primarily acting at the level of the kidneys to regulate plasma potassium and intravascular volume status is being supplemented by evidence of new “off-target” effects of aldosterone in other organ systems. The genomic effects of aldosterone are well known, but there is also evidence for non-genomic effects and these recently identified effects of aldosterone have required a revision in the traditional view of aldosterone’s role in human health and disease. The aim of this article is to review the biological action of aldosterone and the mineralocorticoid receptor leading to subsequent physiologic and pathophysiologic effects involving the vasculature, central nervous system, heart, and kidneys. Furthermore, we outline current evidence evaluating the use of mineralocorticoid receptor antagonists in the treatment of primary aldosteronism, primary hypertension, resistant hypertension, obstructive sleep apnea, heart failure, and chronic kidney disease. PMID:23836977

  18. Discovery of cannabinoid-1 receptor antagonists by virtual screening

    Microsoft Academic Search

    Gil Nam Lee; Kwang Rok Kim; Sung-Hoon Ahn; Myung Ae Bae; Nam Sook Kang

    2010-01-01

    In this work, we tried to find a new scaffold for a CB1 receptor antagonist using virtual screening. We first analyzed structural features for the known cannabinoid-1 receptor antagonists and, then, we built pharmacophore models using the HipHop concept and carried out a docking study based on our homology CB1 receptor 3D structure. The most active compound, including thiazole-4-one moiety,

  19. (D-Phe/sup 12/)bombesin analogues: a new class of bombesin receptor antagonists

    SciTech Connect

    Heinz-Erian, P.; Coy, D.H.; Tamura, M.; Jones, S.W.; Gardner, J.D.; Jensen, R.T.

    1987-03-01

    Previous attempts to develop analogues of bombesin that function as specific receptor antagonists have been unsuccessful. Alteration of the histidine in luteinizing hormone releasing factor has resulted in analogues that function as competitive antagonists. In the present study the authors have used a similar strategy and altered the histidine in bombesin. (D-Phe/sup 12/)bombesin, (D-Phe/sup 12/,Leu/sup 14/)bombesin, and (Try/sup 4/, D-)je/sup 12/) bombesin did not stimulate amylase release from guinea pig pancreatic acini when present alone, but each analog inhibited bombesin-stimulated secretion. For each analog, detectable inhibition occurred at 1 ..mu..M and half-maximal inhibition at 4 ..mu..M. Each analog inhibited amylase release by bombesin and other agonists that stimulate secretion by interacting with bombesin receptors. The analogues of bombesin did not alter stimulation by substance P or other agonists that interact with other receptors. The inhibition of the action of bombesin was competitive with Schild plots having slopes of 1.0. Each analog also inhibited binding of /sup 125/I-labeled (Try/sup 4/) bombesin but not /sup 125/I-labeled substance P. These results demonstrate that (D-Phe/sup 12/) analogues of bombesin function as bombesin receptor antagonists and are the only bombesin receptor antagonists that interact only with the bombesin receptor. Because of their specificity, these analogues may prove useful for defining the role of bombesin in various physiological or pathological processes.

  20. Focal ischemia enhances the adverse effect potential of N-methyl- d-aspartate receptor antagonists in rats

    Microsoft Academic Search

    Wolfgang Löscher; Piotr Wla?; Laszlo Szabo

    1998-01-01

    Recent clinical trials with non-competitive and competitive N-methyl-d-aspartate (NMDA) receptor antagonists in patients with stroke have shown that these patients develop more adverse effects, particularly psychomimetic effects such as hallucinations and agitation, than normal volunteers at equivalent doses. We therefore examined whether such increased adverse effect potential of NMDA antagonists also occurs in a rat model of permanent focal ischemia.

  1. The classification of peripheral 5-HT2-like receptors using tryptamine agonist and antagonist analogues.

    PubMed Central

    Leff, P.; Martin, G. R.; Morse, J. M.

    1986-01-01

    In a previous study, we attempted to verify the classification of 5-hydroxytryptamine2 (5-HT2) receptors in three vascular tissues, by use of the conventional antagonists, ketanserin, spiperone, methysergide and trazodone. However, it was not possible to conclude homogeneity of the receptor type in the three tissues due to the inconsistent behaviour of these antagonists, in particular, their apparently variable affinities between the tissues. These results led to the reliability of the conventional antagonists being questioned as receptor probes. In the present study, a set of tryptamine analogues were investigated in two of the tissues, the rabbit aorta and the rat jugular vein. Unlike the conventional antagonists, these compounds bear a close chemical relation to the natural agonist, 5-HT. In both tissues, alpha, alpha-dimethyltryptamine demonstrated apparently simple competitive antagonism of 5-HT-induced constrictions. Its affinity was estimated to be the same in each case. The affinities and relative efficacies of 5-HT, 5-cyanotryptamine, N,N-dimethyltryptamine and N-benzyl-5-methoxytryptamine were also found to be indistinguishable between the two tissues. Unlike the conventional 5-HT2 receptor antagonists, these tryptamine analogues failed to distinguish between the 5-HT receptors in the rabbit aorta and rat jugular vein implying that they truly belong to the same class. In view of this result, it is suggested that simple tryptamine analogues are more reliable probes for 5-HT receptor classification than ligands which bear little or no chemical relation to the natural agonist. PMID:3801784

  2. Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

    PubMed Central

    Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert; Mathews, James; Snyder, Rodney; Fennell, Tim; Maitra, Rangan

    2015-01-01

    Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS. PMID:23098108

  3. Blood Pressure-Lowering Effect of an Orally Active Vasopressin VI Receptor Antagonist in Mineralocorticoid Hypertension in the Rat

    Microsoft Academic Search

    Louise M. Burrell; Paddy A. Phillips; J. m. Stephenson; J. Risvanis; K. a. Rolls; C. i. Johnston

    Abstract We studied ,the contribution of vasopressin to the maintenance,of high ,blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension ,in the ,rat using the non- peptide orally effective vasopressin ,VI receptor ,antagonist OPC-21268. Binding kinetic studies demonstrated ,that oral OPC-21268 (30 mg\\/kg) acted as a ,competitive ,antagonist at the vasopressin VI receptor ,in DOCA-salt and salt control rats. Basal ,mean ,intra-arterial

  4. 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

  5. Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro.

    PubMed Central

    Clague, R. U.; Eglen, R. M.; Strachan, A. C.; Whiting, R. L.

    1985-01-01

    The action of 'selective' agonists and antagonists at muscarinic receptors mediating ileal contractions, and the rate and force of atrial contractions has been assessed. The effect of nicotinic receptor stimulation, catecholamine release and acetylcholinesterase (AChE) action on muscarinic activity has also been assessed. The nicotinic actions of carbachol did not affect its agonist potency nor the antagonist affinity data obtained when this agonist was used in atrial and ileal preparations. Antagonist data indicated that muscarinic receptors mediating the rate and force of atrial contractions did not differ. Differences in agonist potencies at these two muscarinic receptors were attributable to either differences in intrinsic efficacy or susceptibility to the action of acetylcholinesterase. The small differences in agonist potency observed between atrial and ileal muscarinic receptors were considered not sufficient to indicate receptor heterogeneity. The pirenzepine affinity data indicated that all three receptors are of the M2 type. Affinity data using secoverine and 4-diphenyl-acetoxy-N-methyl piperidine methiodide indicated that ileal and atrial muscarinic receptors differ. Data obtained using gallamine, pancuronium and stercuronium cannot be regarded as indicative of receptor affinity since the antagonism is not competitive; it did nonetheless corroborate the conclusion that ileal and atrial muscarinic receptors are different. PMID:3876860

  6. Fosinopril H(2)-receptor antagonists interaction studies by derivative spectroscopy.

    PubMed

    Sultana, Najma; Arayne, M Saeed; Sana, Aisha

    2007-01-01

    Fosinopril sodium, a phosphinic acid derivative is an angiotensin converting enzyme (ACE) inhibitor, which had been employed for the treatment of hypertension and congestive heart failure; long tem use of ACE inhibitor often result in stress ulcers due to which H(2) receptor antagonists are also concurrently prescribed. The later compete with histamine for H(2) receptors and block gastric acid secretion and some cardiovascular effects of histamine. Our studies are focused on the in vitro availability of fosinopril in presence of commonly used H(2) receptor antagonists. Derivative spectroscopy has been employed for the quantitation of fosinopril and H(2) receptor antagonists followed by linear regression analysis. These studies were carried out in buffers of pH 7.4 and 9 at 37, 48 and 60( masculine)C. Stability constant and thermodynamic function had also been calculated in order to evaluate the reaction mechanism. Commonly prescribed H(2) receptor antagonists like cimetidine, ranitidine and famotidine were used in these studies. Present study clearly indicated that most of the H(2) receptor antagonists studied decreased the availability of fosinopril which conclude that availability of fosinopril can be affected by the concurrent administration of H(2) receptor antagonists. PMID:17337423

  7. Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3 Receptor Antagonists

    PubMed Central

    2015-01-01

    We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor (Ki = 12.8 ?M), our efforts have yielded (1R,2S)-11 (CJ-1882), which has Ki values of 2.7 and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D2 receptors. Evaluation in a ?-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor. PMID:24848155

  8. Why are mineralocorticoid receptor antagonists cardioprotective?

    PubMed Central

    Chai, Wenxia

    2006-01-01

    Two clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effect could not be attributed solely to blockade of the renal MR-mediated effects on blood pressure, and it has therefore been proposed that aldosterone, the endogenous MR agonist, also acts extrarenally, in particular in the heart. Indeed, MR are present in cardiac tissue, and possibly aldosterone synthesis occurs in the heart. This review critically addresses the following questions: (1) is aldosterone synthesized at cardiac tissue sites, (2) what agonist stimulates cardiac MR normally, and (3) what effects are mediated by aldosterone/MR in the heart that could explain the beneficial effects of MR blockade in heart failure? Conclusions are that most, if not all, of cardiac aldosterone originates in the circulation (i.e., is of adrenal origin), and that glucocorticoids, in addition to aldosterone, may serve as the endogenous agonist of cardiac MR. MR-mediated effects in the heart include effects on endothelial function, cardiac fibrosis and hypertrophy, oxidative stress, cardiac inotropy, coronary flow, and arrhythmias. Some of these effects occur via or in synergy with angiotensin II, and involve a non-MR-mediated mechanism. This raises the possibility that aldosterone synthase inhibitors might exert beneficial effects on top of MR blockade. PMID:17075718

  9. Eprosartan mesylate, an angiotensin II receptor antagonist

    PubMed Central

    Qian, Jing-Jing; Hu, Xiu-Rong; Gu, Jianming; Wu, Su-Xiang

    2011-01-01

    The title compound, eprosartan mesylate {systematic name: 2-butyl-1-(4-carb­oxy­benz­yl)-5-[(E)-2-carb­oxy-3-(thio­phen-2-yl)prop-1-en­yl]-1H-imidazol-3-ium methane­sulfonate}, C23H25N2O4S+·CH3O3S?, one of the angiotensin II-receptor antagonists, is effective in regulating hypertension, induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure and glaucoma. In the eprosartan residue, which appears in this crystal in the cationic imidazolium form, the benzene ring plane is almost orthogonal to that of the imidazole ring, making a dihedral angle of 87.89?(2)°. The thio­phene ring forms dihedral angles of 66.54?(2) and 67.12?(2)° with the benzene and imidazole rings, respectively. The imidazolium NH group and the H atom of the aromatic carboxyl group participate in hydrogen bonds with the the O atoms of the anion, thus forming centrosymmetric aggregates made up of two cations and two anions each. The second carboxyl group further links the above-mentioned aggregates through a conventional centrosymmetric hydrogen-bonding motif into infinite chains along [011]. PMID:21754064

  10. DEFICIENCY OF INTERLEUKIN-1 RECEPTOR ANTAGONIST RESPONSIVE TO ANAKINRA

    PubMed Central

    SCHNELLBACHER, CHARLOTTE; CIOCCA, GIOVANNA; MENENDEZ, ROXANNA; AKSENTIJEVICH, IVONA; GOLDBACH-MANSKY, RAPHAELA; DUARTE, ANAM.; RIVAS-CHACON, RAFAEL

    2012-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acutephase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

  11. Identification of a novel conformationally constrained glucagon receptor antagonist.

    PubMed

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences. PMID:24418771

  12. Small-molecule antagonists of the orexin receptors.

    PubMed

    Christopher, John A

    2014-01-01

    The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014. PMID:25489915

  13. The Serotonin 5HT2A Receptors Antagonist M100907 Prevents Impairment in Attentional Performance by NMDA Receptor Blockade in the Rat Prefrontal Cortex

    Microsoft Academic Search

    Carli Mirjana; Marta Baviera; Roberto W Invernizzi; Claudia Balducci

    2004-01-01

    We investigated whether 5-HT2A receptors contribute to the control of attentional performance by glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC). We examined the effects of NMDA receptor blockade in the mPFC on attentional performance by infusing a competitive glutamate NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) into the mPFC of rats performing a task of divided and sustained

  14. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity

    Microsoft Academic Search

    N B Farber; S H Kim; K Dikranian; X P Jiang; C Heinkel

    2002-01-01

    NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative

  15. Discovery of cannabinoid-1 receptor antagonists by virtual screening.

    PubMed

    Lee, Gil Nam; Kim, Kwang Rok; Ahn, Sung-Hoon; Bae, Myung Ae; Kang, Nam Sook

    2010-09-01

    In this work, we tried to find a new scaffold for a CB1 receptor antagonist using virtual screening. We first analyzed structural features for the known cannabinoid-1 receptor antagonists and, then, we built pharmacophore models using the HipHop concept and carried out a docking study based on our homology CB1 receptor 3D structure. The most active compound, including thiazole-4-one moiety, showed an activity value of 125 nM IC(50), with a good PK profile. PMID:20667724

  16. Effect of histamine-2 receptor antagonists on blood alcohol levels

    Microsoft Academic Search

    David S. Weinberg; Daniel Burnham; Jesse A. Berlin

    1998-01-01

    OBJECTIVE: To determine the effect, if any, of histamine type 2 receptor antagonists (H2RAs) on serum alcohol levels under various conditions including type of H2RA receptor antagonist, alcohol dose, and fed status of the subject.\\u000a \\u000a \\u000a STUDY DESIGN: Meta-analysis of the published literature.\\u000a \\u000a \\u000a \\u000a \\u000a DATA SOURCES: Studies were identified by MEDLINE (January 1982 through December 1997) using the key words H2 receptor

  17. Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors.

    PubMed

    Callander, Gabrielle E; Olorunda, Morenike; Monna, Dominique; Schuepbach, Edi; Langenegger, Daniel; Betschart, Claudia; Hintermann, Samuel; Behnke, Dirk; Cotesta, Simona; Fendt, Markus; Laue, Grit; Ofner, Silvio; Briard, Emmanuelle; Gee, Christine E; Jacobson, Laura H; Hoyer, Daniel

    2013-01-01

    Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various "dual" orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [(3)H]-BBAC ((S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the "dual" antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the "dual" antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo. PMID:24376396

  18. In vitro interactions of captopril with H2-receptor antagonists.

    PubMed

    Sultana, Najma; Arayne, M Saeed; Quraish, Reeshanul

    2007-04-01

    Captopril is effective in the treatment of hypertension of all grades of severity. H2-receptors antagonists block gastric acid secretion and some cardiovascular effects of histamine. In view of the fact that, simultaneous administration of both drugs may alter the antihypertensive effect of captopril, present paper deals with the in vitro availability studies of captopril in presence of commonly used H2-receptor antagonists like cimetidine, ranitidine and famotidine. In order to simulate various pH levels in GI tract and to find out the kinetics and energetics of captopril-H2-receptor antagonist interactions, these studies were carried out in buffers of pH 4, 7.4 and 9 at 37 degrees C and at elevated temperatures. These studies clearly indicate that most of the H2-receptor antagonists bind to captopril, forming charge-transfer complexes. As a result, the availability of captopril was affected by the concurrent administration of H2-receptor antagonists. Accordingly coadministration of both the drugs should be avoided. PMID:17416569

  19. TARP Auxiliary Subunits Switch AMPA Receptor Antagonists into Partial Agonists

    Microsoft Academic Search

    Karen Menuz; Robert M. Stroud; Roger A. Nicoll; Franklin A. Hays

    2008-01-01

    Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity

  20. TARP Auxiliary Subunits Switch AMPA Receptor Antagonists into Partial Agonists

    Microsoft Academic Search

    Karen Menuz; Robert M. Stroud; Roger A. Nicoll; Franklin A. Hays

    2007-01-01

    Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity

  1. Adenosine Receptor Antagonists and Retinal Neovascularization in Vivo

    Microsoft Academic Search

    Robert P. Mino; Polyxenie E. Spoerri; Sergio Caballero; Luiz Belardinelli; Italo Biaggioni; Maria B. Grant

    2001-01-01

    PURPOSE. The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was ex- amined in a mouse pup model of oxygen-induced retinopathy. METHODS. A previously described model of oxygen-induced retinal neovascularization in newborn mouse pups was used to examine

  2. Pharmacophore modeling of human adenosine receptor A 2A antagonists

    Microsoft Academic Search

    Zhejun Xu; Feixiong Cheng; Chenxiao Da; Guixia Liu; Yun Tang

    2010-01-01

    Three-dimensional pharmacophore models of human adenosine receptor A2A antagonists were developed based on 23 diverse compounds selected from a large number of A2A antagonists. The best pharmacophore model, Hypo1, contained five features: one hydrogen bond donor , three hydrophobic points\\u000a and one ring aromatic. Its correlation coefficient, root mean square deviation, and cost difference values were 0.955, 0.921\\u000a and 84.4,

  3. Are CB1 Receptor Antagonists Nootropic or Cognitive Impairing Agents?

    PubMed Central

    Varvel, Stephen A.; Wise, Laura E.; Lichtman, Aron H.

    2010-01-01

    For more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB1 receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though a CB1 receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogenous cannabinoid system. Several groups have reported that CB1 receptor antagonists enhance memory duration in a variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB1 receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB1 receptor antagonists elicit a variety of effects, including enhancement of long-term potentiation (LTP), while disrupting long-term depression (LTD) and interfering with transient forms of plasticity, including depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB1 receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB1 receptors may strengthen memory duration, but interferes with extinction of learned behaviors that are associated with traumatic or aversive memories. PMID:20539824

  4. Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

    PubMed Central

    Bendix, Ivo; Serdar, Meray; Herz, Josephine; von Haefen, Clarissa; Nasser, Fatme; Rohrer, Benjamin; Endesfelder, Stefanie; Felderhoff-Mueser, Ursula; Spies, Claudia D.; Sifringer, Marco

    2014-01-01

    Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. PMID:24595240

  5. Opinion: NK3 receptor antagonists: the next generation of antipsychotics?

    PubMed

    Spooren, Will; Riemer, Claus; Meltzer, Herbert

    2005-12-01

    Although current antipsychotic drugs are effective at treating the psychotic (positive) symptoms of schizophrenia, they have one or more serious side effects, including extrapyramidal symptoms, weight gain, cardiovascular liabilities and type II diabetes. However, recent data from clinical trials of selective neurokinin 3 (NK(3)) receptor antagonists in schizophrenia - osanetant and talnetant - have shown significant improvement in positive symptoms, with no major side-effects reported as yet. Here we discuss the preclinical and clinical evidence that indicates that NK(3) receptor antagonists might represent a new approach to the treatment of schizophrenia and possibly other neuropsychiatric disorders. PMID:16341062

  6. Altered trkB neurotrophin receptor activation does not influence the N-methyl- d-aspartate receptor antagonist-mediated neurotoxicity in mouse posterior cingulate cortex

    Microsoft Academic Search

    Jussi Väisänen; Tommi Saarelainen; Eija Koponen; Eero Castrén

    2003-01-01

    Non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists produce toxic effects in the limbic cortex of rodent brain. NMDA antagonists also increase the expression of brain-derived neurotrophic factor (BDNF) mRNA in the same brain areas. The aim of this study was to investigate whether increased BDNF signalling plays a role in the NMDA-mediated toxic effect by using transgenic mice with modified BDNF signalling

  7. TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists.

    PubMed

    Menuz, Karen; Stroud, Robert M; Nicoll, Roger A; Hays, Franklin A

    2007-11-01

    Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity required coexpression of TARPs. A crystal structure of CNQX bound to the TARP-less AMPA receptor ligand-binding domain showed that, although CNQX induces partial domain closure, this movement is not transduced into linker separation, suggesting that TARPs may increase agonist efficacy by strengthening the coupling between domain closure and channel opening. Our results demonstrate that the presence of an auxiliary subunit can determine whether a compound functions as an agonist or antagonist. PMID:17975069

  8. Disubstituted piperidines as potent Orexin (hypocretin) receptor antagonists

    PubMed Central

    Jiang, Rong; Song, Xinyi; Bali, Purva; Smith, Anthony; Bayona, Claudia Ruiz; Lin, Li; Cameron, Michael D.; McDonald, Patricia H.; Kenny, Paul J.

    2012-01-01

    A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure activity relationships (SAR), installation of various groups at the 3–6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction. PMID:22617492

  9. 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

  10. Synthesis of enantiomerically pure pyrrolidinones as endothelin receptor antagonists

    Microsoft Academic Search

    Shripad S. Bhagwat; Candido Gude; Kenneth Chan

    1996-01-01

    Enantiomerically pure pyrrolidinones were synthesized as endothelin receptor antagonists. A [2+2] cycloaddition of an imine and an enantiomerically pure acid chloride gave two diastereomeric ?-lactams which were separated and rearranged to give the enantiomerically pure pyrrolidinones which could be reduced to give the corresponding pyrrolidines.

  11. Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

    PubMed

    Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

    2015-07-01

    Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality. PMID:26106934

  12. Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure

    PubMed Central

    Li, Nanxin; Liu, Rong-Jian; Dwyer, Jason M.; Banasr, Mounira; Lee, Boyoung; Son, Hyeon; Li, Xiao-Yuan; Aghajanian, George; Duman, Ronald S.

    2011-01-01

    Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. Results The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner. PMID:21292242

  13. Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists

    Microsoft Academic Search

    Per-Göran Gillberg; Staffan Sundquist; Lisbeth Nilvebrant

    1998-01-01

    Tolterodine [(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was

  14. A 1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers

    Microsoft Academic Search

    William F. Kiesman; Elfatih Elzein; Jeff Zablocki

    \\u000a Intense efforts of many pharmaceutical companies and academicians in the A1 adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric\\u000a enhancers. The A1AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human\\u000a (h) A1AR subtype (hA1\\u000a K\\u000a i 200-fold selectivity over the

  15. Selective sigma-1 receptor antagonists for the treatment of pain.

    PubMed

    Almansa, Carmen; Vela, José Miguel

    2014-06-01

    The sigma-1 receptor (?1R) is located in areas of the CNS key for pain control and belongs to a unique target class with chaperoning functions over different molecular targets involved in transmission and amplification of nociceptive messages. Preclinical evidence supports a role for ?1R antagonists in the treatment of pain states where hypersensitivity develops as hyperalgesia and allodynia, two common symptoms encountered in neuropathic and other chronic pain conditions. Additionally, ?1R antagonists increase opioid analgesia without increasing opioid-related unwanted effects, which point to their potential use as opioid adjuvant therapy. This review summarizes the structure and function of the ?1R as well as the medicinal chemistry and pharmacological studies directed to the identification of ?1R antagonists for the treatment of pain. PMID:25078137

  16. Transient receptor potential ankyrin 1 (TRPA1) antagonists.

    PubMed

    Preti, Delia; Saponaro, Giulia; Szallasi, Arpad

    2015-01-01

    The transient receptor potential ankyrin 1 (TRPA1) channel is an irritant sensor highly expressed on nociceptive neurons. The clinical use of TRPA1 antagonists is based on the concept that TRPA1 is active during disease states like neuropathic pain. Indeed, in Phase 2a proof-of-concept studies the TRPA1 antagonist GRC17536 has shown efficacy in patients with painful diabetic neuropathy. Moreover, animal studies suggest that the therapeutic value of TRPA1 antagonists extends beyond pain to pruritus, asthma and cough with limited safety concerns. This review provides a comprehensive overview of the patent literature (since 2007) on small-molecule inhibitors of the TRPA1 channel. Despite the clear progress, many unanswered questions remain. Future advancement to Phase 3 studies will assess the real translational potential of this research field. PMID:25853468

  17. Nicotinic receptor antagonists as treatments for nicotine abuse.

    PubMed

    Crooks, Peter A; Bardo, Michael T; Dwoskin, Linda P

    2014-01-01

    Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the ?4?2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at ?3?2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While ?-conotoxin MII (?-CtxMII)-insensitive nAChRs (e.g., ?4?2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, ?-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at ?-CtxMII-sensitive nAChR subtypes that contain ?6 and ?2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, nonquaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1nM) nicotine-evoked DA release in vitro by acting as antagonists at ?-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats. PMID:24484986

  18. Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

    PubMed Central

    Crooks, Peter A.; Bardo, Michael T.; Dwoskin, Linda P.

    2014-01-01

    Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the ?4?2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at ?3?2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While ?-conotoxin MII (?-CtxMII)-insensitive nAChRs (e.g., ?4?2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, ?-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at ?-CtxMII-sensitive nAChR subtypes that contain ?6 and ?2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, non-quaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1 nM) nicotine-evoked DA release in vitro by acting as antagonists at ?-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats. PMID:24484986

  19. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine

    PubMed Central

    Funder, John W

    2013-01-01

    Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as was eplerenone in subsequent heart failure trials. Neither acts as an aldosterone antagonist in the heart as the cardiac MR are occupied by cortisol, which becomes an aldosterone mimic in conditions of tissue damage. The accepted term “MR antagonist”, (as opposed to “aldosterone antagonist” or, worse, “aldosterone blocker”), should be retained, despite the demonstration that they act not to deny agonist access but as inverse agonists. The prevalence of primary aldosteronism is now recognized as accounting for about 10% of hypertension, with recent evidence suggesting that this figure may be considerably higher: in over two thirds of cases of primary aldosteronism therapy including MR antagonists is standard of care. MR antagonists are safe and vasoprotective in uncomplicated essential hypertension, even in diabetics, and at low doses they also specifically lower blood pressure in patients with so-called resistant hypertension. Nowhere are more than 1% of patients with primary aldosteronism ever diagnosed and specifically treated. Given the higher risk profile in patients with primary aldosteronism than that of age, sex, and blood pressure matched essential hypertension, on public health grounds alone the guidelines for first-line treatment of all hypertension should mandate inclusion of a low-dose MR antagonist. PMID:24133375

  20. Combinations of neurokinin receptor antagonists reduce visceral hyperalgesia.

    PubMed

    Kamp, E H; Beck, D R; Gebhart, G F

    2001-10-01

    The effect of selective neurokinin receptor (NKR) antagonists for the NK1R (SR140,333), NK2R (SR48,968), and NK3R (SR142,801) on the visceromotor response to noxious colorectal distension (CRD) was examined. NKR antagonists or vehicle were given intrathecally (i.th.) to rats made hyperalgesic by intracolonic instillation of zymosan or after intracolonic instillation of saline (control). Given alone, the NK1R (up to 3 microg of SR140,333) and NK2R (up to 60 microg of SR48,968) antagonists tested failed to significantly affect responses to the noxious visceral stimulus. However, coadministration of 3 microg of SR140,333 and 60 microg of SR48,968 (both i.th.) significantly reduced responses to noxious CRD (p < 0.05 versus vehicle). The NK3R antagonist (60 microg of SR142,801) significantly reduced responses to noxious CRD when given alone to either hyperalgesic (zymosan-treated) or normal (saline-treated) rats (p < 0.05 versus vehicle for both groups). Responses of rats receiving the NK3R antagonist in combination with either the NK1R or the NK2R antagonist were not different from rats receiving the NK3R antagonist alone. These results suggest that activation of spinal NK1R and NK2R, presumably by their endogenous ligands (substance P and neurokinin A), maintain visceral hyperalgesia and support the notion that activation of NK3R (presumably by neurokinin B) is pronociceptive. PMID:11561069

  1. Endothelin-receptor antagonists in arterial hypertension: Further indications?

    Microsoft Academic Search

    Isabella Sudano; Matthias Hermann; Frank T. Ruschitzka

    2007-01-01

    Endothelin-1 exerts vasoactive, pro-inflammatory, hypertrophic, and profibrotic properties on the heart, kidney, and blood\\u000a vessels. Hence, endothelin-receptor antagonists hold the potential to reduce blood pressure and to prevent complications of\\u000a hypertension, atherosclerosis, and diabetes through blood pressure-independent effects on cardiovascular growth, inflammation,\\u000a and fibrosis. These potentially important effects of endothelin antagonism may contribute to its therapeutic potential in\\u000a hypertension and

  2. Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson disease.

    PubMed

    Mesnage, V; Houeto, J L; Bonnet, A M; Clavier, I; Arnulf, I; Cattelin, F; Le Fur, G; Damier, P; Welter, M L; Agid, Y

    2004-01-01

    The neuropeptides neurokinin B, neurotensin, and anandamide, the endogenous ligands of NK3, NT1, and CB1 receptors respectively, are known to interact with brain dopaminergic transmission. This study evaluated the effects of these three antagonists of the NK3 (SR 142801), neurotensin (SR 48692), and cannabinoid (SR 141716) receptors on the severity of motor symptoms and levodopa-induced dyskinesias after administration of a single dose of levodopa in 24 patients with Parkinson disease. In this exploratory randomized, double-blind, placebo-controlled study, at the dose used, the drugs tested were well tolerated and could not improve parkinsonian motor disability. PMID:15190231

  3. Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists.

    PubMed

    Roser, Patrik; Vollenweider, Franz X; Kawohl, Wolfram

    2010-03-01

    Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action. PMID:20218784

  4. Nonpeptide Angiotensin II Receptor Antagonists. IV. EXP6155 and EXP6803

    Microsoft Academic Search

    Pancras C. Wong; William A. Price Jr.; Andrew T. Chiu; Martin J. M. C. Thoolen; John V. Duncia; Alexander L. Johnson; Pieter B. M. W. M. Timmermans

    2010-01-01

    EXP6155 (2-n-butyl-l-(4-carboxybenzyl)-4-chloroimidazole-5-acetic acid) and EXP6803 (methyl 2-n-butyl-l-(4-(2-carfooxybenzamido)ben2yl)-4-chloroimidazole-5-acetate, sodium salt) are shown to be novel, nonpeptide, antihypertensive, specific angiotensin II receptor antagonists. In rabbit aorta, they competitively inhibited the contractile response to angiotensin II with px2 values of 6.54 and 7.20 and did not alter the response to norepinephrine or KC1. In guinea pig ileum, both agents blocked the responses to

  5. Subglutinol A, an immunosuppressive ?-pyrone diterpenoid from Fusarium subglutinans, acts as an estrogen receptor antagonist.

    PubMed

    Lim, Wonchung; Park, Joonwoo; Lee, Yong Hee; Hong, Jiyong; Lee, YoungJoo

    2015-06-01

    Subglutinol A is an immunosuppressive ?-pyrone diterpenoid isolated from Fusarium subglutinans that exhibits osteogenic activity. Several non-steroid mycotoxins isolated from various strains of Fusarium fungi exhibit female steroid hormone activities. In this study, we characterized the estrogenic activity of subglutinol A (1). Subglutinol A blocked the 17?-estradiol-induced activation of reporter plasmids and endogenous estrogen-responsive target genes in a dose-dependent manner and efficiently destabilized ER proteins as shown using the estrogen receptor antagonist ICI 182,780. Subglutinol A also displaced the specific binding of [(3)H]17?-estradiol from ER in MCF-7 whole-cell ligand binding assays. These data demonstrate the potential of subglutinol A as an ER antagonist though its competition with 17?-estradiol for direct ER association. PMID:25896764

  6. Functionalized Congeners of P2Y1 Receptor Antagonists:

    SciTech Connect

    de Castro, Sonia [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Maruoka, Hiroshi [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hong, Kunlun [ORNL; Kilbey, II, S Michael [ORNL; Costanzi, Stefano [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hechler, Béatrice [University of Strasbourg; Gachet, Christian [EFS-Alsace, Strasbourg, France; Harden, T. Kendall [University of North Carolina School of Medicine; Jacobson, Kenneth A. [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

    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 produce a multivalent conjugate exhibiting a desired biological effect, i.e., antithrombotic action.

  7. Quinazolines as Adenosine Receptor Antagonists: SAR and Selectivity for A2B Receptors

    PubMed Central

    Webb, Thomas R.; Lvovskiy, Dmitriy; Kim, Soon-Ai; Ji, Xiao-duo; Melman, Neli; Linden, Joel; Jacobson, Kenneth A.

    2012-01-01

    We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A2B receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2?-amino-4?-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding Ki value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with Ki values in the micromolar range. Since no enhancement of A2B receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched. PMID:12467710

  8. Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1.

    PubMed

    Chrencik, Jill E; Roth, Christopher B; Terakado, Masahiko; Kurata, Haruto; Omi, Rie; Kihara, Yasuyuki; Warshaviak, Dora; Nakade, Shinji; Asmar-Rovira, Guillermo; Mileni, Mauro; Mizuno, Hirotaka; Griffith, Mark T; Rodgers, Caroline; Han, Gye Won; Velasquez, Jeffrey; Chun, Jerold; Stevens, Raymond C; Hanson, Michael A

    2015-06-18

    Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with at least six cognate G protein-coupled receptors. Herein, we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analyses. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease. PMID:26091040

  9. Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor

    PubMed Central

    Saleem, Huma; Tovey, Stephen C; Molinski, Tedeusz F; Taylor, Colin W

    2014-01-01

    BACKGROUND AND PURPOSE Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels. Interactions of the commonly used antagonists of IP3Rs with IP3R subtypes are poorly understood. EXPERIMENTAL APPROACH IP3-evoked Ca2+ release from permeabilized DT40 cells stably expressing single subtypes of mammalian IP3R was measured using a luminal Ca2+ indicator. The effects of commonly used antagonists on IP3-evoked Ca2+ release and 3H-IP3 binding were characterized. KEY RESULTS Functional analyses showed that heparin was a competitive antagonist of all IP3R subtypes with different affinities for each (IP3R3 > IP3R1 ? IP3R2). This sequence did not match the affinities for heparin binding to the isolated N-terminal from each IP3R subtype. 2-aminoethoxydiphenyl borate (2-APB) and high concentrations of caffeine selectively inhibited IP3R1 without affecting IP3 binding. Neither Xestospongin C nor Xestospongin D effectively inhibited IP3-evoked Ca2+ release via any IP3R subtype. CONCLUSIONS AND IMPLICATIONS Heparin competes with IP3, but its access to the IP3-binding core is substantially hindered by additional IP3R residues. These interactions may contribute to its modest selectivity for IP3R3. Practicable concentrations of caffeine and 2-APB inhibit only IP3R1. Xestospongins do not appear to be effective antagonists of IP3Rs. PMID:24628114

  10. Design and synthesis of N-alkylated saccharins as selective ?-1a adrenergic receptor antagonists

    Microsoft Academic Search

    Jennie B. Nerenberg; Jill M. Erb; Wayne J. Thompson; Hee-Yoon Lee; James P. Guare; Peter M. Munson; Jeffrey M. Bergman; Joel R. Huff; Theodore P. Broten; Raymond S. L. Chang; Tsing B. Chen; Stacey O'Malley; Terry W. Schorn; Ann L. Scott

    1998-01-01

    Benign prostatic hyperplasia can be managed pharmacologically with ?-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the ?-1 a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective ?-1 a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo

  11. From NMDA receptor antagonists to discovery of selective ?? receptor ligands.

    PubMed

    Gitto, Rosaria; De Luca, Laura; Ferro, Stefania; Scala, Angela; Ronsisvalle, Simone; Parenti, Carmela; Prezzavento, Orazio; Buemi, Maria Rosa; Chimirri, Alba

    2014-01-01

    Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward ?? receptor (Ki values of 10nM and 20 nM, respectively). Thus, in this case the discovery of new ?? receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors. PMID:24290063

  12. 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

  13. NMDA Receptors Mediate Synaptic Competition in Culture

    PubMed Central

    She, Kevin; Craig, Ann Marie

    2011-01-01

    Background Activity through NMDA type glutamate receptors sculpts connectivity in the developing nervous system. This topic is typically studied in the visual system in vivo, where activity of inputs can be differentially regulated, but in which individual synapses are difficult to visualize and mechanisms governing synaptic competition can be difficult to ascertain. Here, we develop a model of NMDA-receptor dependent synaptic competition in dissociated cultured hippocampal neurons. Methodology/Principal Findings GluN1 -/- (KO) mouse hippocampal neurons lacking the essential NMDA receptor subunit were cultured alone or cultured in defined ratios with wild type (WT) neurons. The absence of functional NMDA receptors did not alter neuron survival. Synapse development was assessed by immunofluorescence for postsynaptic PSD-95 family scaffold and apposed presynaptic vesicular glutamate transporter VGlut1. Synapse density was specifically enhanced onto minority wild type neurons co-cultured with a majority of GluN1 -/- neighbour neurons, both relative to the GluN1 -/- neighbours and relative to sister pure wild type cultures. This form of synaptic competition was dependent on NMDA receptor activity and not conferred by the mere physical presence of GluN1. In contrast to these results in 10% WT and 90% KO co-cultures, synapse density did not differ by genotype in 50% WT and 50% KO co-cultures or in 90% WT and 10% KO co-cultures. Conclusions/Significance The enhanced synaptic density onto NMDA receptor-competent neurons in minority coculture with GluN1 -/- neurons represents a cell culture paradigm for studying synaptic competition. Mechanisms involved may include a retrograde ‘reward’ signal generated by WT neurons, although in this paradigm there was no ‘punishment’ signal against GluN1 -/- neurons. Cell culture assays involving such defined circuits may help uncover the rules and mechanisms of activity-dependent synaptic competition in the developing nervous system. PMID:21935408

  14. Naturally Occurring Eccentric Cleavage Products of Provitamin A ?-Carotene Function as Antagonists of Retinoic Acid Receptors*

    PubMed Central

    Eroglu, Abdulkerim; Hruszkewycz, Damian P.; dela Sena, Carlo; Narayanasamy, Sureshbabu; Riedl, Ken M.; Kopec, Rachel E.; Schwartz, Steven J.; Curley, Robert W.; Harrison, Earl H.

    2012-01-01

    ?-Carotene is the major dietary source of provitamin A. Central cleavage of ?-carotene catalyzed by ?-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of ?-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are ?-apocarotenals and ?-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the ?-apocarotenoids significantly activated RARs. Importantly, however, ?-apo-14?-carotenal, ?-apo-14?-carotenoic acid, and ?-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that ?-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. ?-Apo-13-carotenone and the ?-apo-14?-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3–5 nm ?-apo-13-carotenone was present in human plasma. These findings suggest that ?-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary ?-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer. PMID:22418437

  15. Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols.

    PubMed

    Liu, Genyan; Furuta, Kenjiro; Nakajima, Hiromitsu; Ozoe, Fumiyo; Ozoe, Yoshihisa

    2014-09-01

    ?-Aminobutyric acid (GABA) receptors are important targets of parasiticides/insecticides. Several 4-substituted analogs of the partial GABAA receptor agonist 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) were synthesized and examined for their antagonism of insect GABA receptors expressed in Drosophila S2 cells or Xenopus oocytes. Thio-4-PIOL showed weak antagonism of three insect GABA receptors. The antagonistic activity of Thio-4-PIOL was enhanced by introducing bicyclic aromatic substituents into the 4-position of the isothiazole ring. The 2-naphthyl and the 3-biphenylyl analogs displayed antagonist potencies with half maximal inhibitory concentrations in the low micromolar range. The 2-naphthyl analog induced a parallel rightward shift of the GABA concentration-response curve, suggesting competitive antagonism by these analogs. Both compounds exhibited weak insecticidal activities against houseflies. Thus, the orthosteric site of insect GABA receptors might be a potential target site of insecticides. PMID:25112550

  16. 3D pharmacophore models for thromboxane A(2) receptor antagonists.

    PubMed

    Wei, Jing; Liu, Yixi; Wang, Songqing

    2009-10-01

    Thromboxane A(2) (TXA(2)) is an endogenous arachidonic acid derivative closely correlated to thrombosis and other cardiovascular diseases. The action of TXA(2) can be effectively inhibited with TXA(2) receptor antagonists (TXRAs). Previous studies have attempted to describe the interactions between the TXA(2) receptor and its ligands, but their conclusions are still controversial. In this study, ligand-based computational drug design is used as a new and effective way to investigate the structure-activity relationship of TXRAs. Three-dimensional pharmacophore models of TXRAs were built with HypoGenRefine and HipHop modules in CATALYST software. The optimal HypoGenRefine model was developed on the basis of 25 TXRAs. It consists of two hydrophobic groups, one aromatic ring, one hydrogen-bond acceptor and four excluded volumes. The optimal HipHop model contains two hydrophobic groups and two hydrogen-bond acceptors. These models describe the key structure-activity relationship of TXRAs, can predict their activities, and can thus be used to design novel antagonists. PMID:19263096

  17. A search for selective antagonists at M2 muscarinic receptors.

    PubMed Central

    Barlow, R. B.; Shepherd, M. K.

    1985-01-01

    Isolated preparations of guinea-pig ileum and atria have been used to estimate the dose-ratios produced by antagonists at muscarinic receptors. Experiments with 4-diphenyl-acetoxy-N-methylpiperidine (4DAMP) metho-salts and with its isomer, 3DAMP methiodide, indicate that these are only slightly affected by the choice of physiological salt solution, the choice of agonist and the presence or absence of hexamethonium. Methyl or chloro groups in the p-position of the two benzene rings in 4DAMP metho-salts markedly reduce affinity and selectivity. When the two benzene rings are linked together, as in the fluorene-9-carboxylic ester, the affinity for the receptors in the atria is comparable with that of 4DAMP methobromide but that for the ileum is about half, so the selectivity is reduced. When the rings are linked as in the xanthene-9-carboxylic ester, the affinity for receptors in both tissues is greater than that of 4DAMP methobromide but there is less selectivity. When two molecules of 4DAMP are linked together by a polymethylene chain of from 4 to 12 carbon atoms the effects on affinity for muscarinic receptors in the guinea-pig ileum are different from those on affinity for muscarinic receptors in guinea-pig atria. The pentamethylene compound is the most selective: compared with 4DAMP methobromide it has slightly less affinity for receptors in the ileum but much less affinity for receptors in the atria. The effects of the compounds in antagonizing the actions of carbachol on atrial rate are not markedly different from their effects in antagonizing its actions on the force of the atrial contractions. PMID:3839706

  18. In silico binding characteristics between human histamine H 1 receptor and antagonists

    Microsoft Academic Search

    Xiaojian Wang; Qian Yang; Minyong Li; Dali Yin; Qidong You

    2010-01-01

    It is widely acknowledged that the H1 receptor antagonists have important therapeutic significance in the treatment of various allergic disorders, but little was\\u000a known about the binding mode between the receptor and antagonists since the crystal structure of G-protein coupling receptors\\u000a (GPCRs) were hard to obtain. In this paper, a theoretical three-dimensional model of human histamine H1 receptor (HHR1) was

  19. Pharmacological analysis of agonist-antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay.

    PubMed Central

    Durant, P. A.; Shankley, N. P.; Welsh, N. J.; Black, J. W.

    1991-01-01

    1. Agonist-antagonist interactions at acetylcholine (ACh) muscarinic receptors have been analysed by use of an improved urinary bladder assay, isolated and intact, from the mouse. With 5-methylfurmethide as agonist, validated cumulative concentration-effect curves were obtained in less than 7 min by re-dosing before the response plateaux began to fade. 2. The pKB value estimated for pirenzepine was 6.76. The pKB values estimated for atropine and N-methylatropine from data obtained at concentrations which produced dose-ratios greater than 20 and 60 were 8.90 and 9.58, respectively. 3. The deviation from simple competitive behaviour at low dose-ratios with atropine and N-methylatropine was consistent with the operation of saturable antagonist removal processes. The deviation observed with atropine was corrected by pre-incubation with methylbutyrate, an alternative substrate for 'atropine esterase'. 4. The simple competitive behaviour of N-methylatropine was restored following pre-incubation with the neuronal choline uptake blocker hemicholinium-3 (HC-3). However, the pKB estimated for N-methylatropine under these conditions was low. This latter result could be accounted for by the observed behaviour of HC-3 as a competitive antagonist of ACh muscarinic receptors (pKB = 4.01). 5. We conclude that the modified mouse urinary bladder assay is suitable for the quantitative analysis of muscarinic receptor interactions. In addition, we postulate the existence of a previously undescribed uptake mechanism for quaternary muscarinic receptor antagonists. PMID:1786508

  20. Potent dual antagonists of endothelin and angiotensin II receptors derived from ?-phenoxyphenylacetic acids (Part III)

    Microsoft Academic Search

    Thomas F. Walsh; Kenneth J. Fitch; David L. Williams; Kathryn L. Murphy; Nancy A. Nolan; Douglas J. Pettibone; Raymond S. L. Chang; Stacey S. O'Malley; Bradley V. Clineschmidt; Daniel F. Veber; William J. Greenlee

    1995-01-01

    Screening a collection of ?-phenoxyphenylacetic acid derived angiotensin II antagonists identified weak actives in an endothelin receptor binding assay. Synthetic modification of one of these leads has provided L-746,072 (13), a highly potent dual antagonist of angiotensin II and endothelin receptors.

  1. Effect of a specific endothelin A receptor antagonist on murine lupus nephritis

    Microsoft Academic Search

    Tsukasa Nakamura; Isao Ebihara; Yasuhiko Tomino; Hikaru Koide

    1995-01-01

    Effect of a specific endothelin A receptor antagonist on murine lupus nephritis. The present study was designed to assess whether a specific endothelin A (ETA) receptor antagonist, FR139317, affects the progression of lupus nephritis and affects transcription of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP)-1, and accumulation of ECM proteins in the renal

  2. Octylonium bromide interacts competitively with the PAF receptor.

    PubMed

    Barone, D; Maggi, C A; Baroldi, P; Giachetti, A; Meli, A

    1989-01-01

    To clarify the nature of the interaction of octylonium bromide with the PAF receptor, saturation studies of 3H-PAF binding were made in the presence of increasing concentrations of the radioligand (from 0.06 to 7.4 nM) and of octylonium bromide (1 X 10(-8), 5 X 10(-8) and 1 X 10(-7) M) or of a potent PAF antagonist L 652,731 (2.5 X 10(-7) M), or in the absence of competing drugs. Saturation binding data were plotted according to the non-linear fitting analysis and to Scatchard transformation. Both mathematical models indicated that the presence of added drugs decreased the affinity of the complex 3H-PAF/PAF receptors, leaving unaffected the maximum number of PAF binding sites. Receptor parameters in the absence of competitors were: KD = 1.2 nM, Bmax = 950 fmoles 3H-PAF bound/10(8) platelets. Octylonium bromide increased, in a concentration-dependent manner, KD values from 1.5 to 2.1 nM, while Bmax ranged from 910 to 980 fmoles 3H-PAF specifically bound/10(8) platelets. Likewise, L 652,731 did not influence Bmax (980 fmoles) but increased KD (1.9 nM). The binding behaviour of octylonium bromide and L 652,731 indicates that the two compounds inhibit competitively the binding of 3H-PAF to its receptors. PMID:2557193

  3. Straub tail reaction in mice treated with ?(1) receptor antagonist in combination with methamphetamine.

    PubMed

    Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Uhl, George R; Tanaka, Koh-Ichi; Nishiyama, Nobuyoshi; Takemura, Motohiko

    2012-10-30

    Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific ? receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative ?(1) receptor agonist) and partially by PB 28 (a putative ?(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative ?(1) receptor antagonist), but not SM-21, a putative ?(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective ?-agonist), suggesting that the STR may be mediated by activation of opioid receptor system. PMID:22981417

  4. MEN?11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist

    PubMed Central

    Catalioto, R-M; Criscuoli, M; Cucchi, P; Giachetti, A; Giannotti, D; Giuliani, S; Lecci, A; Lippi, A; Patacchini, R; Quartara, L; Renzetti, A R; Tramontana, M; Arcamone, F; Maggi, C A

    1998-01-01

    The pharmacological profile was studied of MEN?11420, or cyclo{[Asn(?-D-GlcNAc)-Asp-Trp-Phe-Dap-Leu]cyclo(2?-5?)}, a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK2 receptor antagonist MEN?10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2?-5?)).MEN?11420 competitively bound with high affinity to the human NK2 receptor stably transfected in CHO cells, displacing radiolabelled [125I]-neurokinin?A and [3H]-SR?48968 with Ki values of 2.5±0.7?nM (n=6) and 2.6±0.4?nM (n=3), respectively.MEN?11420 showed negligible binding affinity (pIC50<6) at 50 different receptors (including tachykinin NK1 and NK3 receptors) and ion channels.In the rabbit isolated pulmonary artery and rat urinary bladder MEN?11420 potently and competitively antagonized tachykinin NK2 receptor-mediated contractions (pKB=8.6±0.07, n=10, and 9.0±0.04, n=12; Schild plot slope=?1.06 (95% c.l.=?1.3; ?0.8) and ?1.17 (95% c.l.=?1.3; ?1.0), respectively). MEN?11420 produced an insurmountable antagonism at NK2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the effect of MEN?11420 was reverted by washout and an apparent pKB of 10.2±0.14, n=?9, and 9.8±0.15, n=9, was calculated in the hamster trachea and mouse urinary bladder, respectively.MEN?11420 showed low affinity (pKB<6) at guinea-pig and rat tachykinin NK1 (guinea-pig ileum and rat urinary bladder) and NK3 (guinea-pig ileum and rat portal vein) receptors. On the whole, the affinities (potency and selectivity) showed by MEN?11420 for different tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN?10627.The in vivo antagonism of the contractions produced by [?Ala8]neurokinin?A(4–10) (1?nmol?kg?1) was observed after intravenous (dose range: 1–10?nmol?kg?1), intranasal (3–10?nmol?kg?1), intrarectal (30–100?nmol?kg?1) and intraduodenal (100–300?nmol?kg?1) administration of MEN?11420. MEN?11420 was more potent (about 10 fold) and longer lasting than its parent compound MEN?10627, possibly due to a greater metabolic stability.A dose of MEN?11420 (100?nmol?kg?1, i.v.), that produced potent and long lasting inhibition of the contraction of the rat urinary bladder induced by challenge with the NK2 selective receptor agonist [?Ala8]neurokinin?A(4–10) (10–300?nmol?kg?1), was without effect on the responses produced by the NK1 receptor selective agonist [Sar9]substance?P sulphone (1–10?nmol?kg?1).These findings indicate that MEN?11420 is a potent and selective tachykinin NK2 receptor antagonist. The introduction of a sugar moiety did not produce major changes in the affinity profile of this antagonist as compared to MEN?10627, but markedly improved its in vivo potency and duration of action. With these characteristics, MEN?11420 is a suitable candidate for studying the pathophysiological significance of tachykinin NK2 receptors in humans. PMID:9484857

  5. Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

    PubMed Central

    Herbrechter, Robin; Ziemba, Paul M.; Hoffmann, Katrin M.; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

    2015-01-01

    The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT3 receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT3 receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT3Areceptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from Aurantii, Ginseng, Zingiberis, Atractylodis and Glycyrrhiza inhibited the 5-HT3A receptor response, whereas the tinctures of Poria cocos, Jujubae and Pinellia exhibited no effect. Surprisingly, the strongest antagonism was found for Glycyrrhiza, whereas the Zingiberis tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT3A receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT3 receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from Glycyrrhiza species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from Aurantii inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of 5-HT3A receptors. Thus, this study reveals new 5-HT3A receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito.

  6. Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids.

    PubMed

    Herbrechter, Robin; Ziemba, Paul M; Hoffmann, Katrin M; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

    2015-01-01

    The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT3 receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT3 receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT3Areceptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from Aurantii, Ginseng, Zingiberis, Atractylodis and Glycyrrhiza inhibited the 5-HT3A receptor response, whereas the tinctures of Poria cocos, Jujubae and Pinellia exhibited no effect. Surprisingly, the strongest antagonism was found for Glycyrrhiza, whereas the Zingiberis tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT3A receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT3 receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from Glycyrrhiza species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from Aurantii inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of 5-HT3A receptors. Thus, this study reveals new 5-HT3A receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito. PMID:26191003

  7. GLP-1 receptor antagonist as a potential probe for pancreatic {beta}-cell imaging

    SciTech Connect

    Mukai, Eri [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan) [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Japan Association for the Advancement of Medical Equipment, Tokyo (Japan); Toyoda, Kentaro [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan)] [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Kimura, Hiroyuki [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto (Japan)] [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto (Japan); Kawashima, Hidekazu [Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto (Japan)] [Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Fujimoto, Hiroyuki [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan) [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Japan Association for the Advancement of Medical Equipment, Tokyo (Japan); Ueda, Masashi [Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto (Japan)] [Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto (Japan); Temma, Takashi [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto (Japan)] [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto (Japan); Hirao, Konomu; Nagakawa, Kenji [Research and Development Division, Arkray, Inc., Kyoto (Japan)] [Research and Development Division, Arkray, Inc., Kyoto (Japan); Saji, Hideo [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto (Japan)] [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto (Japan); Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan) [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto (Japan); CREST of Japan Science and Technology Cooperation (JST), Kyoto (Japan)

    2009-11-20

    We examined exendin(9-39), an antagonist of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), as a potential probe for imaging of pancreatic {beta}-cells. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Binding assay showed competitive inhibition of [{sup 125}I]BH-exendin(9-39) binding by non-radioactive exendin(9-39). To assess in vivo selectivity, the biodistribution was evaluated by intravenous administration of [{sup 125}I]BH-exendin(9-39) to mice. Radioactivity of harvested pancreas reached highest levels at 60 and 120 min among organs examined except lung. Pre-administration of excess non-radioactive exendin(9-39) remarkably and specifically blocked the radioactivity of pancreas. After [{sup 125}I]BH-exendin(9-39) injection into transgenic mice with pancreatic {beta}-cells expressing GFP, fluorescent and radioactive signals of sections of pancreas were evaluated with an image analyzer. Imaging analysis showed that the fluorescent GFP signals and the radioactive signals were correspondingly located. Thus, the GLP-1R antagonist exendin(9-39) may serve as a useful probe for pancreatic {beta}-cell imaging.

  8. Endothelin Receptor Antagonists: New Hope for Renal Protection?

    PubMed

    Tobe, Sheldon; Kohan, Donald E; Singarayer, Ranjit

    2015-07-01

    Endothelin receptor antagonists (ERAs) have the potential to be a new paradigm in the treatment of chronic kidney disease (CKD). ERAs inhibit the effects of endothelin-1 (ET-1), which is known to promote CKD by causing renal cellular injury, proteinuria, inflammation, fibrosis, and hypertrophy. ERAs have been extensively studied preclinically in models of CKD and now in a large clinical trial to determine their effect on slowing the progression of CKD. Initial clinical trials show promise with regard to ERA effects on reducing proteinuria in patients with diabetic nephropathy (DN) who are already on renin-angiotensin system (RAS) blocking agents. A common side effect of peripheral edema has been consistently reported in clinical trials using ERAs; hence, finding a safe balance between renoprotective actions and side effects needs to be achieved. PMID:26068660

  9. Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 receptor antagonists.

    PubMed

    Hostetler, Greg; Dunn, Derek; McKenna, Beth Ann; Kopec, Karla; Chatterjee, Sankar

    2014-05-01

    Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists have been disclosed. One potent member from the lactam series, racemic compound 14 (Ki of 2.6 nM in binding assay, IC50 of 15 nM in functional cAMP antagonism assay) was separated into corresponding enantiomers that displayed the effect of chirality on binding potency (Ki of 1.6 nM and 3000 nM, respectively). The potent enantiomer displayed an IC50 of 8 nM in cAMP antagonism assay, selectivity against a number of family members as well as brain permeability in rats after 6h post oral administration. PMID:24704027

  10. 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.

  11. Selective ?-1A adrenergic receptor antagonists. effects of pharmacophore regio- and stereochemistry on potency and selectivity

    Microsoft Academic Search

    Michael A. Patane; Robert M. DiPardo; RoseAnn P. Price; Raymond S. L. Chang; Richard W. Ransom; Stacey S. O'Malley; Jerry Di Salvo; Mark G. Bock

    1998-01-01

    The anti-anxiety agent ipsapirone has been shown to have modest affinity for ?-1 receptors. We disclose the discovery of potent ?-1 a receptor subtype selective antagonists based on the ipsapirone structure which possess selectivity versus the 5-HT receptors tested. These antagonists were obtained by tethering a saccharin ring to 4-phenyl-3-carboxyethyl piperidines. The design principles which led to this structural motif

  12. Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen–glucose depletion

    PubMed Central

    Wu, X; Kihara, T; Hongo, H; Akaike, A; Niidome, T; Sugimoto, H

    2010-01-01

    BACKGROUND AND PURPOSE Several clinical trials and in vivo animal experiments have suggested that blockade of angiotensin receptor type 1 (AT1) improves ischaemic outcomes. However, the mechanism(s) underlying these effects has not been elucidated. Here, we have investigated the protective effects of pretreatment with AT1 receptor antagonists, losartan or telmisartan, against ischaemic insult to neurons in vitro. EXPERIMENTAL APPROACH Primary rat neuron–astrocyte co-cultures and astrocyte-defined medium (ADM)-cultured pure astrocyte cultures were prepared. Ischaemic injury was modelled by oxygen–glucose depletion (OGD) and lactate dehydrogenase release after OGD was measured with or without AT1 receptor antagonists or agonists (L162313), AT2 receptor antagonist (PD123319) or agonist (CGP-42112A) pretreatment, for 48 h. Activity of glutamate transporter 1 (GLT-1) was evaluated by [3H]-glutamate uptake assays, after AT1 receptor agonists or antagonists. Immunoblot and real-time PCR were used for analysis of protein and mRNA levels of GLT-1. KEY RESULTS AT1 receptor agonists augmented OGD-induced cellular damage, which was attenuated by AT1 receptor antagonists. AT1 receptor antagonists also suppressed OGD-induced extracellular glutamate release, reactive oxygen species production and nitric oxide generation. GLT-1 expression and glutamate uptake activity were significantly enhanced by AT1 receptor antagonists and impaired by AT1 receptor agonists. AT1 receptor stimulation suppressed both ADM-induced GLT-1 protein expression and mRNA levels. AT1b receptor knock-down with siRNA enhanced GLT-1 expression. In postnatal (P1–P21) rat brains, protein levels of GLT-1 and AT1 receptors were inversely correlated. CONCLUSIONS AND IMPLICATIONS Suppression of AT1 receptor stimulation induced GLT-1 up-regulation, which ameliorated effects of ischaemic injury. PMID:20718738

  13. Activity of an interleukin 1 receptor antagonist in rabbit models of uveitis.

    PubMed

    Rosenbaum, J T; Boney, R S

    1992-04-01

    Interleukin 1 has been implicated in intraocular inflammation. The availability of a cloned, recombinant interleukin 1 receptor antagonist has enabled us to test the role of interleukin 1 in specific models of uveitis in New Zealand white rabbits. Seventy-five micrograms of interleukin 1 receptor antagonist injected intravitreally resulted in a 97% reduction in aqueous humor cells present 6 hours after intravitreal injection of 10 ng of human interleukin 1 alpha. Disruption of the blood aqueous barrier was prevented by the receptor antagonist (mean +/- SD aqueous humor protein of 0.6 +/- 0.1 g/L in rabbits treated with interleukin 1 receptor antagonist vs 32.2 +/- 9.9 g/L in controls). Lower doses of interleukin 1 produced more modest but significant inhibition. Despite the activity of interleukin 1 receptor antagonist in inhibiting interleukin 1-induced inflammation, interleukin 1 receptor antagonist did not produce significant reduction in inflammation subsequent to an active Arthus reaction or subsequent to the intravitreal injection of 125 ng of endotoxin. A potential explanation of these observations is that cytokines in addition to interleukin 1 may be present in sufficient quantities to produce intraocular inflammation or that the effects of interleukin 1 may be primarily intracellular (intracrine) and therefore resistant to the activity of exogenously administered receptor antagonist. PMID:1532889

  14. Reversible and syntopic interaction between angiotensin receptor antagonists on Chinese hamster ovary cells expressing human angiotensin II type 1 receptors.

    PubMed

    Vanderheyden, P M; Fierens, F L; De Backer, J; Vauquelin, G

    2000-04-15

    Evidence for a competitive type of interaction between angiotensin II type 1 (AT(1)) antagonists on Chinese hamster ovary cells expressing the human AT(1) receptor (CHO-AT(1)) was obtained by analyzing the binding of [(3)H]-2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H- ben zimidazoline-7-carboxylic acid ([(3)H]candesartan) and by measuring the AT-induced production of inositol phosphates. The AT(1) antagonists candesartan, 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]+ ++imid azole-5-carboxylic acid (EXP3174), or 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl- 4-yl)methyl]imidazole (losartan) produced a concentration-dependent increase in the apparent K(d) values of [(3)H]candesartan in saturation binding experiments, while the B(max) values were unchanged. Furthermore, the dissociation rate of the radioligand initiated by 1 microM unlabelled candesartan was not changed in the presence of 10 microM losartan, 10 microM EXP3174, or 10 microM irbesartan (2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5-yl)b iph enyl-4-yl) methyl]2-imidazolin-5-one)). Preincubation of the CHO-AT(1) cells with candesartan, EXP3174, and irbesartan caused a reduction in the maximal AT-induced inositol mono-, bis-, and trisphosphate production. This insurmountable effect was reversed in the presence of 1 microM losartan. In line with this finding, the insurmountable antagonist concentration-inhibition curves at 10 microM AT were shifted to the right in the presence of losartan. For candesartan this effect was concentration-dependent, yielding a pK(B) value for losartan of 7.7, which is similar to the pK(B) from previously obtained AT concentration-response curves. Finally, the dissociation rate of candesartan, EXP3174, irbesartan, and losartan was determined by measuring the recovery of AT responses after antagonist pretreatment and washing of the cells with medium containing 1 microM losartan to prevent re-association of the insurmountable antagonists. In addition, similar kinetic data were obtained from the slowing of the [(3)H]candesartan association rate to antagonist preincubated cells. PMID:10692557

  15. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs.

    PubMed

    Munoz, Miguel; Covenas, Rafael; Esteban, Francisco; Redondo, Maximino

    2015-06-01

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, which are involved in their viability. This overexpression suggests the possibility of specific treatment against tumour cells using NK-1 receptor antagonists, thus promoting a considerable decrease in the side effects of the treatment. This strategy opens up new approaches for cancer treatment, since these antagonists, after binding to their molecular target, induce the death of tumour cells by apoptosis, exert an antiangiogenic action and inhibit the migration of tumour cells. The use of NK-1 receptor antagonists such as aprepitant (used in clinical practice) as antitumour agents could be a promising innovation. The value of aprepitant as an antitumour agent could be determined faster than for less wellknown compounds because many studies addressing its safety and characterization have already been completed. The NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific drugs against tumour cells; and these antagonists could be new candidate anti-cancer drugs. PMID:25963269

  16. The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy.

    PubMed

    Twele, Friederike; Bankstahl, Marion; Klein, Sabine; Römermann, Kerstin; Löscher, Wolfgang

    2015-08-01

    The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy. PMID:25839899

  17. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.

    PubMed

    Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; La?ewska, Dorota; Adem, Abdu; Kie?-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. PMID:24776492

  18. Inhaled muscarinic acetylcholine receptor antagonists for treatment of COPD.

    PubMed

    Montuschi, P; Macagno, F; Valente, S; Fuso, L

    2013-01-01

    Bronchodilators, generally administered via metered dose or dry powder inhalers, are the mainstays of pharmacological treatment of stable COPD. Inhaled long-acting beta-agonists (LABA) and anticholinergics are the bronchodilators primarily used in the chronic treatment of COPD. Anticholinergics act as muscarinic acetylcholine receptor antagonists and are frequently preferred over beta-agonists for their minimal cardiac stimulatory effects and greater efficacy in most studies. Their therapeutic efficacy is based on the fact that vagally mediated bronchoconstriction is the major reversible component of airflow obstruction in patients with COPD. However, bronchodilators are effective only on the reversible component of airflow obstruction, which by definition is limited, as COPD is characterized by a fixed or poorly reversible airflow obstruction. Inhaled anticholinergic antimuscarinic drugs approved for the treatment of COPD include ipratropium bromide, oxitropium bromide and tiotropium bromide. Ipratropium bromide, the prototype of anticholinergic bronchodilators, is a short-acting agent. Oxitropium bromide is administered twice a day. Tiotropium bromide, the only long-acting antimuscarinic agent (LAMA) currently approved, is administered once a day. Newer LAMAs including aclidinium bromide and glycopyrrolate bromide are currently in phase III development for treatment of COPD. Some new LAMAs, including glycocpyrrolate, are suitable for once daily administration and, unlike tiotropium, have a rapid onset of action. New LAMAs and their combination with ultra-LABA and, possibly, inhaled corticosteroids, seem to open new perspectives in the management of COPD. Dual-pharmacology muscarinic antagonist-beta2 agonist (MABA) molecules present a novel approach to the treatment of COPD by combining muscarinic antagonism and beta2 agonism in a single molecule. PMID:22963553

  19. Biomolecular recognition of antagonists by ?7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure-activity relationships studies.

    PubMed

    Peng, Wei; Ding, Fei

    2015-08-30

    As the key constituent of ligand-gated ion channels in the central nervous system, nicotinic acetylcholine receptors (nAChRs) and neurodegenerative diseases are strongly coupled in the human species. In recently years the developments of selective agonists by using nAChRs as the drug target have made a large progress, but the studies of selective antagonists are severely lacked. Currently these antagonists rest mainly on the extraction of partly natural products from some animals and plants; however, the production of these crude substances is quite restricted, and artificial synthesis of nAChR antagonists is still one of the completely new research fields. In the context of this manuscript, our primary objective was to comprehensively analyze the recognition patterns and the critical interaction descriptors between target ?7 nAChR and a series of the novel compounds with potentially antagonistic activity by means of virtual screening, molecular docking and molecular dynamics simulation, and meanwhile these recognition reactions were also compared with the biointeraction of ?7 nAChR with a commercially natural antagonist - methyllycaconitine. The results suggested clearly that there are relatively obvious differences of molecular structures between synthetic antagonists and methyllycaconitine, while the two systems have similar recognition modes on the whole. The interaction energy and the crucially noncovalent forces of the ?7 nAChR-antagonists are ascertained according to the method of Molecular Mechanics/Generalized Born Surface Area. Several amino acid residues, such as B/Tyr-93, B/Lys-143, B/Trp-147, B/Tyr-188, B/Tyr-195, A/Trp-55 and A/Leu-118 played a major role in the ?7 nAChR-antagonist recognition processes, in particular, residues B/Tyr-93, B/Trp-147 and B/Tyr-188 are the most important. These outcomes tally satisfactorily with the discussions of amino acid mutations. Based on the explorations of three-dimensional quantitative structure-activity relationships, the structure-antagonistic activity relationships of antagonists and the characteristics of ?7 nAChR-ligand recognitions were received a reasonable summary as well. These attempts emerged herein would not only provide helpful guidance for the design of ?7 nAChR antagonists, but shed new light on the subsequent researches in antagonistic mechanism. PMID:25963024

  20. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    PubMed Central

    Pertwee, R.G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with ?9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors. PMID:20166927

  1. Acute effects of AMPA-type glutamate receptor antagonists on intermale social behavior in two mouse lines bidirectionally selected for offensive aggression.

    PubMed

    Vekovischeva, O Yu; Aitta-aho, T; Verbitskaya, E; Sandnabba, K; Korpi, E R

    2007-01-01

    Involvement of AMPA-type glutamate receptors in the regulation of social behavior has been suggested by experiments with mice deficient for the GluR-A subunit-containing AMPA receptors showing reduced intermale aggression. In the present study, effects of AMPA receptor antagonists on mouse social behavior towards unfamiliar Swiss-Webster males on a neutral territory were tested using male subjects from the Turku Aggressive (TA) and Turku Non-Aggressive (TNA) mouse lines bidirectionally selected for high and low levels of offensive aggression. The drugs were the competitive antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), and the non-competitive antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine (GYKI 52466). In TA mice, CNQX and NBQX decreased the biting component of aggressive structure, while GYKI 52466 suppressed all aggressive manifestations. All drugs increased anxiety-like behavior towards the partner. In TNA mice, NBQX activated mouse social behavior and ambivalent aggression, while CNQX and GYKI 52466 only increased anxiety. Thus, AMPA receptor antagonists affect aggressive behaviors in TA mice supporting the idea that AMPA receptors are involved in the modulation of agonistic impulsive behavioral pattern. GYKI 52466 appeared to be the most selective and efficacious in suppressing the aggression. PMID:17537494

  2. Neuroprotection is associated with ?-adrenergic receptor antagonists during cardiac surgery: Evidence from 2,575 patients

    Microsoft Academic Search

    David W. Amory; Alina Grigore; John K. Amory; Mark A. Gerhardt; William D. White; Peter K. Smith; Debra A. Schwinn; J. G. Reves; Mark F. Newman

    2002-01-01

    Objective: To determine the impact of perioperative ?-adrenergic receptor (?AR) antagonist administration on neurologic complications. Design: Observational database analysis. Setting: A clinical investigation at a single tertiary academic medical center. Participants: Elective coronary artery bypass graft surgical patients operated on in the period 1994-1996. Interventions: Patients were divided into 2 groups: (1) patients given ?AR antagonist–blocking drugs in the perioperative

  3. Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists.

    PubMed

    Joshi, Pramod; Anderson, Corey; Binch, Hayley; Hadida, Sabine; Yoo, Sanghee; Bergeron, Danielle; Decker, Caroline; terHaar, Ernst; Moore, Jonathan; Garcia-Guzman, Miguel; Termin, Andreas

    2014-02-01

    Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. PMID:24405707

  4. Vasopressin antagonists allow demonstration of a novel type of vasopressin receptor in the rat adenohypophysis.

    PubMed

    Jard, S; Gaillard, R C; Guillon, G; Marie, J; Schoenenberg, P; Muller, A F; Manning, M; Sawyer, W H

    1986-08-01

    The ligand specificity of rat adenohypophyseal vasopressin receptors was directly compared to that of peripheral receptors of the V1 and V2 types. For this purpose a series of 15 recently designed vasopressin antagonists was used. The affinities of these antagonists for rat adenohypophyseal membranes were deduced from the determination of the concentration-dependent inhibition of [3H]vasopressin binding. In parallel experiments the corticotropin (or anti-corticotropin)-releasing activities of the tested peptides were determined on freshly dispersed rat adenohypophyseal cells. All peptides tested which were found to be antagonists of the vasopressor and antidiuretic responses to vasopressin in vivo behaved as antagonists of vasopressin-induced corticotropin release. There was a close correlation between the relative affinities of the analogues tested for binding to adenohypophyseal membranes and their relative potencies in inhibiting vasopressin-induced corticotropin release, indicating that the detected vasopressin-binding sites are the receptors involved in the vasopressin effect on corticotropin secretion. No correlation could be demonstrated between anti-corticotropin-releasing activities and either anti-antidiuretic or antivasopressor potencies of the antagonists tested. A direct comparison of the ligand specificities of adenohypophyseal receptors on the one hand, and V1 (hepatic) and V2 (renal) receptors on the other hand, showed that most of the antagonists discriminated very efficiently between adenohypophyseal and either hepatic or renal receptors. The selectivity index reaches values as high as 260,000 for desGly(NH2)9 [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-D-O-ethyl-tyrosine, 4-valine] arginine vasopressin. It is concluded that adenohypophyseal receptors represent a novel type of vasopressin receptors. Based on the observation that adenohypophyseal receptors, like hepatic or vascular V1 receptors, do not appear to be coupled to adenylate cyclase, we propose that adenohypophyseal receptors could be designated as V1b receptors as opposed to the V1a receptors previously characterized on liver and blood vessels. PMID:3016500

  5. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist

    PubMed Central

    2014-01-01

    Background Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide. Methods We investigated the binding of Ilantide to IL-1 receptor type I (IL-1RI) using surface plasmon resonance, the inhibition of Il-1?-induced activation of nuclear factor ?B (NF-?B) in HEK-Blue cells that contained an IL-1?-sensitive reporter, the secretion of TNF-? in macrophages, protection against IL-1-induced apoptosis in neonatal pancreatic islets, and the penetration of Ilantide through the blood–brain barrier using competitive enzyme-linked immunosorbent assay (ELISA). We studied the effects of the peptide on social behavior and memory in rat models of lipopolysaccharide (LPS)- and amyloid-induced neuroinflammation, respectively, and its effect in a rat model of experimental autoimmune enchephalomyelitis. Results Ilantide bound IL-1RI, inhibited the IL-1?-induced activation of NF-?B, and inhibited the secretion of TNF-? in vitro. Ilantide protected pancreatic islets from apoptosis in vitro and reduced inflammation in an animal model of arthritis. The peptide penetrated the blood–brain barrier. It reduced the deficits in social activity and memory in LPS- and amyloid-treated animals and delayed the development of experimental autoimmune enchephalomyelitis. Conclusions These findings indicate that Ilantide is a novel and potent IL-1RI antagonist that is able to reduce inflammatory damage in the central nervous system and pancreatic islets. PMID:24490798

  6. Food intake and rumen motility in dwarf goats. Effects of some serotonin receptor agonists and antagonists

    Microsoft Academic Search

    F. Kaya; C. T. M. van Duin; G. H. Veenendaal; A. S. J. P. A. M. van Miert

    1992-01-01

    The serotonergic regulation of feeding behaviour has not so far been studied in ruminants. Therefore, the effects of some serotonin (5-HT) receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats.

  7. Hit-to-lead studies: the discovery of potent, orally bioavailable triazolethiol CXCR2 receptor antagonists.

    PubMed

    Baxter, Andrew; Bennion, Colin; Bent, Janice; Boden, Kerry; Brough, Steve; Cooper, Anne; Kinchin, Elizabeth; Kindon, Nicholas; McInally, Tom; Mortimore, Mike; Roberts, Bryan; Unitt, John

    2003-08-18

    A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45. PMID:12873480

  8. Hit-to-Lead studies: The discovery of potent, orally bioavailable triazolethiol CXCR2 receptor antagonists

    Microsoft Academic Search

    Andrew Baxter; Colin Bennion; Janice Bent; Kerry Boden; Steve Brough; Anne Cooper; Elizabeth Kinchin; Nicholas Kindon; Tom McInally; Mike Mortimore; Bryan Roberts; John Unitt

    2003-01-01

    A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.

  9. Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications.

    PubMed

    Simonsen, Klaus B; Juhl, Karsten; Steiniger-Brach, Björn; Nielsen, Søren Møller

    2010-07-01

    The cloning of the three tachykinin receptors in the late 1980s formed the basis of intense preclinical research efforts into the systems relating to the tachykinin receptors, as well as compound screening campaigns. Remarkably, orally active non-peptide antagonists were successfully identified for all three of the tachykinin receptors, providing tools for further evaluation of the pharmacology of these receptor systems. The NK3 receptor (mammalian tachykinin receptor 3), which exhibited a discrete expression pattern and the modulatory regulation of various transmitter systems in the CNS, has attracted significant interest. Preclinical studies demonstrated that the NK3 receptor might be a promising target for CNS disorders, and clinical trials with non-peptide NK3 receptor antagonists have been performed for indications such as schizophrenia, major depressive disorder, panic attacks and Parkinson's disease. In particular, the positive results of the schizophrenia meta-trial with osanetant increased the focus on the NK3 receptor system and its clinical potential. Consequently, a significant number of patents covering non-peptide antagonists for the NK3 receptor have been published during the past decade. This review describes the most recent NK3 receptor antagonists (published from 2004 to 2009), which are classified into seven unique templates. PMID:20597024

  10. Different affinity states of alpha-1 adrenergic receptors defined by agonists and antagonists in bovine aorta plasma membranes

    SciTech Connect

    Jagadeesh, G.; Deth, R.C.

    1987-11-01

    Evidence for a nonlinear relationship between alpha-1 adrenergic receptor occupancy and tissue responses, together with the finding of different affinity states for agonist binding, has raised the possibility of functional heterogeneity of alpha-1 adrenergic receptors. We have conducted studies to examine: 1) binding characteristics of (/sup 3/H)prazosin, 2) competition of antagonists at these sites and 3) different affinity states of the receptor for agonists and modulation of these states by 5'-guanylylimidodiphosphate (Gpp(NH)p). A plasma membrane-enriched vesicular fraction (F2; 15%/33% sucrose interphase) was prepared from the muscular medial layer of bovine thoracic aorta. (/sup 3/H)Prazosin binding was characterized by a monophasic saturation isotherm (KD = 0.116 nM, Bmax = 112 fmol/mg of protein). Antagonist displacement studies yielded a relative potency order of prazosin greater than or equal to WB4104 much greater than phentolamine greater than corynanthine greater than yohimbine greater than or equal to idazoxan greater than rauwolscine. Competition curves for unlabeled prazosin, WB4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane) and phentolamine were shallow and were best modeled to two binding sites with picomolar and nanomolar KD values. Gpp(NH)p was without effect on antagonist affinity. Agonist (epinephrine, norepinephrine and phenylephrine) competition with (/sup 3/H)prazosin binding was biphasic with pseudo-Hill slopes less than 1.0. Binding was best described by a two-site model in which the average contribution of high affinity sites was 23% of total binding. KD values for the high affinity site ranged from 2.9 to 18 nM, and 3.9 to 5.0 microM for the low affinity site.

  11. Synthesis and Biological Evaluation of Cyclopentaquinoline Derivatives as Nonsteroidal Glucocorticoid Receptor Antagonists.

    PubMed

    Eda, Masahiro; Kuroda, Tomoko; Kaneko, Satoshi; Aoki, Yoshiyuki; Yamashita, Masami; Okumura, Chieko; Ikeda, Yoshitaka; Ohbora, Tomoko; Sakaue, Masaki; Koyama, Natsumi; Aritomo, Keiichi

    2015-06-25

    The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid receptor antagonist. The compound displayed potent in vitro activity, high selectivity over other steroid hormone receptors, and significant antidepressant-like activity in vivo. PMID:25978072

  12. Xanthine derivatives as antagonists at A 1 and A 2 adenosine receptors

    Microsoft Academic Search

    U. Schwabe; D. Ukena; M. J. Lohse

    1985-01-01

    A variety of alkylxanthines has been comparatively examined as antagonists of A1 adenosine receptors in rat fat cells, rat and bovine cerebral cortex and of A2 adenosine receptors in human platelets. With few exceptions all xanthine derivatives with 7-position substituents such as diprophylline, proxyfylline, pentoxifylline and etofylline were less potent antagonists than xanthine itself which hadKi-values of 170 µmol\\/l (A1)

  13. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone

    Microsoft Academic Search

    Jacqueline B. McCrea; Anup K. Majumdar; Michael R. Goldberg; Marian Iwamoto; Cynthia Gargano; Deborah L. Panebianco; Michael Hesney; Christopher R. Lines; Kevin J. Petty; Paul J. Deutsch; M. Gail Murphy; Keith M. Gottesdiener; D. Ronald Goldwater; Robert A. Blum

    2003-01-01

    Background: Aprepitant is a neurokinin1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids

  14. Effect of histamine H 4 receptor antagonist on allergic rhinitis in mice

    Microsoft Academic Search

    Yuji Takahashi; Yoto Kagawa; Kana Izawa; Rie Ono; Masaaki Akagi; Chiaki Kamei

    2009-01-01

    The aim of this study was to clarify the effect of histamine H4 receptor antagonist, JNJ7777120 (1-[(5-Chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine) on allergic rhinitis in mice. We measured allergic symptoms (sneezing and nasal rubbing), serum total IgE and the levels of cytokines in nasal lavage fluid. Histamine H4 receptor antagonist, JNJ7777120, caused the dose-dependent inhibition of nasal symptoms by single and repeated intranasal administrations;

  15. Identification of small molecule antagonists of the human mas-related gene-X1 receptor

    Microsoft Academic Search

    Priya Kunapuli; Seungtaek Lee; Wei Zheng; Melissa Alberts; Oleg Kornienko; Rebecca Mull; Anthony Kreamer; Jong-Ik Hwang; Melvin I. Simon; Berta Strulovici

    2006-01-01

    The recently identified mas-related-gene (MRG) family of receptors, located primarily in sensory neurons of the dorsal root ganglion, has been implicated in the perception of pain. Thus, antagonists of this class of receptors have been postulated to be useful analgesics. Toward this end, we developed a cell-based beta-lactamase (BLA) reporter gene assay to identify small molecule antagonists of the human

  16. 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment.

    PubMed

    Rossé, Gérard; Schaffhauser, Hervé

    2010-01-01

    Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and schizophrenia. The 5-HT(6) receptor is an attractive target for the development of cognitive enhancers due to its unique localization and pharmacology. 5-HT(6) receptor antagonists have been shown to modulate multiple neurotransmitter systems and therefore enhance cognition in preclinical studies. This premise translated into the clinical efficacy of the 5-HT(6) receptor antagonist SB-742457 in mild-to-moderate AD patients. Advances in the understanding of the structure-activity-relationship, the design of novel 5-HT(6) receptor ligands and their potential application for the treatment of CI are reviewed. PMID:20166958

  17. Noncompetitive Antagonist Binding Sites in the Torpedo Nicotinic Acetylcholine Receptor Ion Channel. Structure?Activity Relationship Studies Using Adamantane Derivatives †

    Microsoft Academic Search

    Hugo R. Arias; James R. Trudell; Erin Z. Bayer; Brent Hester; Elizabeth A. McCardy; Michael P. Blanton

    2003-01-01

    We used a series of adamantane derivatives to probe the structure of the phencyclidine locus in either the resting or desensitized state of the nicotinic acetylcholine receptor (AChR). Competitive radioligand binding and photolabeling experiments using well-characterized noncompetitive antagonists such as the phencyclidine analogue (piperidyl-3,4-3H(N))-N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine (( 3H)- TCP), (3H)ethidium, (3H)tetracaine, (14C)amobarbital, and 3-(trifluoromethyl)-3-(m-(125I)iodophenyl)- diazirine ((125I)TID) were performed. Thermodynamic and structure-function relationship

  18. De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.

    PubMed

    Nugiel, David A; Krumrine, Jennifer R; Hill, Daniel C; Damewood, James R; Bernstein, Peter R; Sobotka-Briner, Cynthia D; Liu, Jianwei; Zacco, Anna; Pierson, M Edward

    2010-02-25

    We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor. PMID:20088516

  19. A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists

    Microsoft Academic Search

    Sophie Dix; Gary Gilmour; Slavinka Potts; Janice W. Smith; Mark Tricklebank

    2010-01-01

    Rationale  The range of cognitive and psychotomimetic effects produced by antagonists of the N-methyl-D-aspartate (NMDA) receptor has lead to widespread usage of these molecules as pharmacological models of cognitive\\u000a impairment for drug discovery. Historically, NMDA receptor antagonists have been used interchangeably on the assumption that\\u000a they produce analogous effects.\\u000a \\u000a \\u000a \\u000a \\u000a Objectives  To profile a subset of these antagonists across a novel within-subject cognitive

  20. The sigma-1 receptor antagonist PB212 reduces the Ca²?-release through the inositol (1, 4, 5)-trisphosphate receptor in SK-N-SH cells.

    PubMed

    Gasparre, Giuseppe; Abate, Carmen; Berardi, Francesco; Cassano, Giuseppe

    2012-06-01

    Sigma-1 receptors are specifically located at the endoplasmic reticulum-mitochondrion interface, but upon stimulation by ligands or under prolonged cellular stress, they translocate to other areas of the cell. Sigma-1 receptors are involved in the regulation of intracellular [Ca(2+)] by affecting the Ca(2+)-influx or the release from intracellular stores. In SK-N-SH cells, we measured the affinity of 4-methyl-1-[4-(6-methoxynaphthalen-1-yl)butyl]piperidine (PB212) at sigma-1 receptor by using a competition binding assay with specific radioligand; we obtained a K(i) value=316 ± 19 nM. PB212 also showed an antiproliferative effect in SK-N-SH cells (EC(50)=32 ± 4 ?M) but had no effect in MCF7 cells, which only express sigma-2 receptor; these findings suggest that PB212 behaves as a sigma-1 receptor antagonist. We have studied the effect of PB212 on Ca(2+) homeostasis of the SK-N-SH cell line with the fluorescent probe Fura-2. 100 ?M PB212 induced a Ca(2+)-efflux from the endoplasmic reticulum through the inositol (1, 4, 5)-trisphosphate (IP(3)) receptor. Moreover, [PB212] ranging from 1 to 100?M reduced the Ca(2+)-response, triggered by carbachol or bradykinin that engage the phospholipase C/IP(3) pathway; such a response is generally increased by sigma-1 receptor agonists. On the other hand, PB212 did not reduce the Ca(2+)-response mediated by IP(3) in LoVo cells, which do not express neither sigma-1 nor sigma-2 receptors, and in MCF7 cells. The fact that the activity of the sigma-1 receptor can be experimentally modulated by agonists and antagonists supports the intriguing hypothesis that some endogenous molecules, unknown at the moment, modulate the sigma-1 receptor and its cellular targets. PMID:22465185

  1. RS 39604: a potent, selective and orally active 5-HT4 receptor antagonist.

    PubMed Central

    Hegde, S. S.; Bonhaus, D. W.; Johnson, L. G.; Leung, E.; Clark, R. D.; Eglen, R. M.

    1995-01-01

    1. Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2. In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding pKi estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi < 6.5) for 5-HT1A, 5-HT2C, 5-HT3, alpha 1c, D1, D2, M1, M2, AT1, B1 and opioid mu receptors and moderate affinity for sigma 1, (pKi = 6.8) and sigma 2 (pKi = 7.8) sites. 3. In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30-300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope = 1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2 approximately 10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582507

  2. Pharmacophore modeling of dual angiotensin II and endothelin A receptor antagonists.

    PubMed

    Xue, Wei-Zhe; Lü, Wei; Zhou, Zhi-Ming; Wang, Zhan-Li

    2009-09-01

    Three-dimensional pharmacophore models were generated for AT1 and ET(A) receptors based on highly selective AT1 and ET(A) antagonists using the program Catalyst/HipHop. Both the best pharmacophore model for selective AT1 antagonists (Hypo-AT(1)-7) and ETA antagonists (Hypo-ET(A)-1) were obtained through a careful validation process. All five features contained in Hypo-AT(1)-7 and Hypo-ET(A)-1 (hydrogen-bond acceptor (A), hydrophobic aliphatic (Z), negative ionizable (N), ring aromatic (R), and hydrophobic aromatic (Y)) seem to be essential for antagonists in terms of binding activity. Dual AT1 and ET(A) receptor antagonists (DARAs) can map to both Hypo-AT(1)-7 and Hypo-ET(A)-1, separately. Comparison of Hypo-AT(1)-7 and Hypo-ET(A)-1, not only AT1 and ET(A) antagonist pharmacophore models consist of essential features necessary for compounds to be highly active and selective toward their corresponding receptor, but also have something in common. The results in this study will act as a valuable tool for designing and researching structural relationship of novel dual AT1 and ET(A) receptor antagonists. PMID:20055175

  3. Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide.

    PubMed

    Arai, Kazune; Kashiwazaki, Aki; Fujiwara, Yoko; Tsuchiya, Hiroyoshi; Sakai, Nobuya; Shibata, Katsushi; Koshimizu, Taka-aki

    2015-02-15

    A group of synthetic substance P (SP) antagonists, such as [Arg(6),D-Trp(7,9),N(Me)Phe(8)]-substance P(6-11) and [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance P, bind to a range of distinct G-protein-coupled receptor (GPCR) family members, including V1a vasopressin receptors, and they competitively inhibit agonist binding. This extended accessibility enabled us to identify a GPCR subset with a partially conserved binding site structure. By combining pharmacological data and amino acid sequence homology matrices, a pharmacological lineage of GPCRs that are sensitive to these two SP antagonists was constructed. We found that sensitivity to the SP antagonists was not limited to the Gq-protein-coupled V1a and V1b receptors; Gs-coupled V2 receptors and oxytocin receptors, which couple with both Gq and Gi, also demonstrated sensitivity. Unexpectedly, a dendrogram based on the amino acid sequences of 222 known GPCRs showed that a group of receptors sensitive to the SP antagonists are located in close proximity to vasopressin/oxytocin receptors. Gonadotropin-releasing peptide receptors, located near the vasopressin receptors in the dendrogram, were also sensitive to the SP analogs, whereas ?1B adrenergic receptors, located more distantly from the vasopressin receptors, were not sensitive. Our finding suggests that pharmacological lineage analysis is useful in selecting subsets of candidate receptors that contain a conserved binding site for a ligand with broad-spectrum binding abilities. The knowledge that the binding site of the two broad-spectrum SP analogs partially overlaps with that of distinct peptide agonists is valuable for understanding the specificity/broadness of peptide ligands. PMID:25592317

  4. Inhibitory effects of histamine H 4 receptor antagonists on experimental colitis in the rat

    Microsoft Academic Search

    Csaba Varga; Krisztina Horvath; Aniko Berko; Robin L. Thurmond; Paul J. Dunford; Brendan J. R. Whittle

    2005-01-01

    The histamine H4 receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H1 receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H4 receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked

  5. The Effects of Glutamate and GABA Receptor Antagonists on Nicotine-induced Neurotransmitter Changes in Cognitive Areas

    Microsoft Academic Search

    S. Fallon; E. Shearman; H. Sershen; A. Lajtha

    2007-01-01

    In the present study, we tested the effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter\\u000a changes in the hippocampal (dorsal and ventral) and cortical (medial temporal and prefrontal) brain areas of conscious freely\\u000a moving rats via microdialysis. Both the antagonists and nicotine were administered intracerebrally. The antagonists tested\\u000a were NMDA, AMPA–kainate, and metabotropic glutamate receptor subtype antagonists (MK801,

  6. Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis.

    PubMed

    Rojas, Camilo; Raje, Mithun; Tsukamoto, Takashi; Slusher, Barbara S

    2014-01-01

    Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK1) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT3 receptor antagonist became available. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV. PMID:24184669

  7. Screening of 5-HT1A Receptor Antagonists using Molecularly Imprinted Polymers

    PubMed Central

    O’Connor, Naphtali A.; Paisner, David A.; Huryn, Donna; Shea, Kenneth J.

    2011-01-01

    Molecular imprinting produces network polymers with recognition sites for imprint molecules. The high binding affinity and selectivity in conjunction with the polymers’ physical robustness positions molecular imprinted polymers (MIPs) as candidates for use as preliminary screens in drug discovery. As such, MIPs can serve as crude mimics of native receptors. In an effort to evaluate the relationship between MIPs and native receptors, imprinted polymers for WAY-100635, an antagonist of the serotonin (5-HT) receptor subtype 5-HT1A were prepared. The resulting MIP P(WAY) was evaluated as an affinity matrix in the screening of serotonin receptor antagonists with known affinities for the native receptor. Rough correlations in affinity between the synthetic P(WAY) and native receptor 5-HT1A were found. These findings provide some support for the analogy between MIPs and native receptors and their possible use as surrogates. PMID:17284006

  8. ?-Phenoxyphenylacetic acid derived angiotensin II antagonists with low nanomolar AT 1\\/AT 2 receptor subtype affinity (Part II)

    Microsoft Academic Search

    Thomas F. Walsh; Kenneth J. Fitch; Raymond S. L. Chang; Kristie A. Faust; Tsing-Bau Chen; Salah D. Kivlighn; Gloria J. Zingaro; Victor J. Lotti; Peter K. S. Siegl; Arthur A. Patchett; William J. Greenlee

    1995-01-01

    Directed synthesis and pharmacological evaluation in a recently described class of ?-phenoxyphenylacetic acid bearing angiotensin II (AII) receptor antagonists has afforded further potent AT1-selective AII antagonists. Substitution in the central aromatic ring significantly increases AT2 receptor affinity such that the n-propyl derivative 7g displayed low nanomolar potency at both AT1 and AT2 receptor subtypes.

  9. Negative selection of CD4+ CD8+ thymocytes by T-cell receptor peptide antagonists.

    PubMed Central

    Page, D M; Alexander, J; Snoke, K; Appella, E; Sette, A; Hedrick, S M; Grey, H M

    1994-01-01

    Antigen-induced activation of T cells can be specifically inhibited by antigen analogs that have been termed T-cell receptor peptide antagonists. These antagonists appear to act by inducing the formation of nonstimulatory or partially stimulatory complexes between T-cell receptors and the major histocompatibility complex molecules presenting the peptides. Herein, we have investigated the effect of T-cell receptor peptide antagonists on thymocyte negative selection. First, peptide antagonists were identified for the cytochrome c-specific T-cell clone AD10. These peptides were then tested for their ability to induce negative selection in an in vitro model system using thymocytes from mice transgenic for the AD10 T-cell receptor. Though unable to induce mature T-cell activation, the T-cell receptor peptide antagonists induced deletion of CD4+ CD8+ thymocytes. These results suggest that negative selection of CD4+ CD8+ thymocytes can be induced by T-cell receptor interactions of a lower affinity than those required for mature T-cell activation. Images PMID:7909610

  10. M 3 muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation, hyperresponsiveness and remodeling in mice

    Microsoft Academic Search

    Rui Cao; Xin-Wei Dong; Jun-Xia Jiang; Xiao-Feng Yan; Jun-Shan He; Yang-Mei Deng; Fen-Fen Li; Meng-Jing Bao; Yi-Cheng Xie; Xiao-Ping Chen; Qiang-Min Xie

    2011-01-01

    M3 muscarinic receptors are localized on inflammatory cells, airway smooth muscle, and submucosal glands, known to mediate bronchoconstriction, mucus secretion, and airway remodeling. It is hypothesized bencycloquidium bromide (BCQB), a novel M3 receptor antagonist, might have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation.

  11. In vitro inhibitory effect of SR 27417, a potent platelet-activating factor (PAF) receptor antagonist,

    E-print Network

    Paris-Sud XI, Université de

    Short Note In vitro inhibitory effect of SR 27417, a potent platelet-activating factor (PAF) receptor antagonist, on the PAF-induced bovine platelet aggregation Miriam BASTOS DA SILVAa, Annie of the platelet-activating factor (PAF) receptor, on PAF-induced platelet aggregation was studied in blood

  12. In silico binding characteristics between human histamine H1 receptor and antagonists.

    PubMed

    Wang, Xiaojian; Yang, Qian; Li, Minyong; Yin, Dali; You, Qidong

    2010-09-01

    It is widely acknowledged that the H(1) receptor antagonists have important therapeutic significance in the treatment of various allergic disorders, but little was known about the binding mode between the receptor and antagonists since the crystal structure of G-protein coupling receptors (GPCRs) were hard to obtain. In this paper, a theoretical three-dimensional model of human histamine H(1) receptor (HHR1) was developed on the basis of recently reported high resolution structures of human A(2A) adenosine receptor, human beta(2)-adrenoceptor and turkey beta(1)-adrenoceptor. Furthermore, three representative H(1) receptor antagonists were chosen for docking studies. Subsequently, a qualitative pharmacophore model was developed by Hiphop algorithm based on the docking conformations of these three antagonists. In this paper, active environment, certain key residues, and the corresponding pharmacophore features of H(1) receptor were identified by such combinations of receptor-based and ligand-based approaches, which would give sufficient guidance for the rational design of novel antihistamine agents. PMID:20179978

  13. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment.

    PubMed

    Edvinsson, Lars

    2015-08-01

    Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one of the major limitations in the use of triptans. However their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question of where is the target site(s) for antimigraine action. The gepants are small molecules that can partially pass the blood-brain barrier (BBB) and therefore, might have effects in the CNS. However, antibodies are large molecules and have limited possibility to pass the BBB, thus effectively excluding them from having a major site of action within the CNS. It is suggested that the antimigraine site should reside in areas not limited by the BBB such as intra- and extracranial vessels, dural mast cells and the trigeminal system. In order to clarify this topic and surrounding questions, it is important to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB. PMID:25731075

  14. Synthesis and biological evaluation of substituted desloratadines as potent arginine vasopressin V2 receptor antagonists.

    PubMed

    Mu, Shuai; Liu, Ying; Gong, Min; Liu, Deng-Ke; Liu, Chang-Xiao

    2014-01-01

    Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate. PMID:24566331

  15. Involvement of the neurotrophin and cannabinoid systems in the mechanisms of action of neurokinin receptor antagonists.

    PubMed

    Hassanzadeh, Parichehr; Hassanzadeh, Anna

    2011-12-01

    The anxiolytic- and antidepressant-like effects of the neurokinin (NK) receptor antagonists have been shown in behavioral studies. According to the involvement of neurotrophin signaling in the mechanisms of action of psychotropic agents, we aimed to investigate whether the selective NK(1), NK(2), or NK(3) receptor antagonists (GR-205171, SR48968, and SR142801, respectively) affect nerve growth factor (NGF) contents in the brain regions involved in the modulation of emotions. To gain a mechanistical insight into the process by which the NK antagonists regulate brain NGF levels, we evaluated the role of the cannabinoid system which is linked to depression and/or antidepressant effects and appears to interact with neurotrophin signaling. According to the results, single injection of the NK receptor antagonists (3, 5, and 10mg/kg, i.p.) into gerbils did not alter NGF or endocannabinoid (eCB) levels quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. Three-week administration of 10mg/kg NK antagonists significantly elevated both NGF and eCB levels in brain-region specific fashion. Pre-application of the CB(1) receptor neutral antagonist AM4113 (5.6mg/kg) prevented the elevation of NGF or eCB induced by the NK antagonists. AM4113 showed no effect by itself. We conclude that the cannabinoid system is implicated in the mechanisms of action of NK receptor antagonists including the upregulation of brain NGF levels. PMID:21316930

  16. Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor

    PubMed Central

    van Koppen, Chris J; de Gooyer, Marcel E; Karstens, Willem-Jan; Plate, Ralf; Conti, Paolo GM; van Achterberg, Tanja AE; van Amstel, Monique GA; Brands, Jolanda HGM; Wat, Jesse; Berg, Rob JW; Lane, J Robert D; Miltenburg, Andre MM; Timmers, C Marco

    2012-01-01

    BACKGROUND AND PURPOSE Graves' disease (GD) is an autoimmune disease in which the thyroid is overactive, producing excessive amounts of thyroid hormones, caused by thyroid-stimulating hormone (TSH) receptor-stimulating immunoglobulins (TSIs). Many GD patients also suffer from thyroid eye disease (Graves' ophthalmopathy or GO), as TSIs also activate TSH receptors in orbital tissue. We recently developed low molecular weight (LMW) TSH receptor antagonists as a novel therapeutic strategy for the treatment of GD and GO. Here, we determined the molecular pharmacology of a prototypic, nanomolar potent LMW TSH receptor antagonist, Org 274179-0. EXPERIMENTAL APPROACH Using CHO cells heterogeneously expressing human TSH receptors and rat FRTL-5 cells endogenously expressing rat TSH receptors, we determined the potency and efficacy of Org 274179-0 at antagonizing TSH- and TSI-induced TSH receptor signalling and its cross-reactivity at related follicle-stimulating hormone and luteinizing hormone receptors. We analysed the allosteric mode of interaction of Org 274179-0 and determined whether it is an inverse agonist at five naturally occurring, constitutively active TSH receptor mutants. KEY RESULTS Nanomolar concentrations of Org 274179-0 completely inhibited TSH (and TSI)-mediated TSH receptor activation with little effect on the potency of TSH, in accordance with an allosteric mechanism of action. Conversely, increasing levels of TSH receptor stimulation only marginally reduced the antagonist potency of Org 274179-0. Org 274179-0 fully blocked the increased basal activity of all the constitutively active TSH receptor mutants tested with nanomolar potencies. CONCLUSIONS AND IMPLICATIONS Nanomolar potent TSH receptor antagonists like Org 274179-0 have therapeutic potential for the treatment of GD and GO. PMID:22014107

  17. Nonpeptide antagonists of neuropeptide receptors: Tools for research and therapy

    E-print Network

    Paris-Sud XI, Université de

    to be considered potential neurotransmitters. In addition, numerous receptors and receptor subtypes that recognize. Indeed, knowledge about the functional role of classical neurotransmitters has been mostly based

  18. A peripherally selective diphenyl purine antagonist of the CB1 receptor

    PubMed Central

    Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Mathews, James; Snyder, Rodney; Fennell, Tim; Marusich, Julie A.; Wiley, Jenny L.; Seltzman, Herbert; Maitra, Rangan

    2014-01-01

    Antagonists of the CB1 receptor can be useful in the treatment of several diseases including obesity, diabetes, and liver disease. However, to date, the only clinically approved CB1 receptor antagonist, rimonabant, was withdrawn due to adverse CNS related side effects such as depression and suicidal ideation. Since rimonabant’s withdrawal, several groups have begun pursuing peripherally selective CB1 antagonists. These compounds are expected to be devoid of undesirable CNS related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors within target tissues. Reported here are our latest results toward development of a peripherally selective analog of the diphenyl purine CB1 antagonist otenabant 1. Compound 9 (N-{1-[8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of ?9-THC through the CB1 receptor. PMID:24041123

  19. Elevation of Interleukin 1 Receptor Antagonist in the Stratum Corneum of Sun-exposed and Ultraviolet B-irradiated Human Skin

    Microsoft Academic Search

    Tetsuji Hirao; Hiroe Aoki; Tomoko Yoshida; Yoshihisa Sato; Hironobu Kamoda

    1996-01-01

    Keratinocytes produce not only interleukin 1 (IL-1) but also IL-1 receptor antagonist (IL-1ra), a competitive inhibitor of IL-1. Because little is known about the presence of IL-1ra in the stratum corneum, we examined the content of IL-1ra in the stratum corneum, especially the balance between IL-1 and IL-1ra.IL-l? and IL-1ra, but not IL-1?, were detected in the tape-stripped stratum corneum

  20. The clinically available NMDA receptor antagonist, memantine, exhibits relative safety in the developing rat brain

    Microsoft Academic Search

    Simon M. Manning; Griffin Boll; Erin Fitzgerald; Debra B. Selip; Joseph J. Volpe; Frances E. Jensen

    2011-01-01

    The N-methyl-d-aspartate glutamate receptor (NMDAR) has been implicated in preterm brain injury (periventricular leukomalacia (PVL)) and represents a potential therapeutic target. However, the antagonist dizocilpine (MK-801) has been reported to increase constitutive neuronal apoptosis in the developing rat brain, limiting its clinical use in the developing brain. Memantine is another use-dependent NMDAR antagonist with shorter binding kinetics and has been

  1. A novel class of 5HT 2a receptor antagonists: Aryl aminoguanidines

    Microsoft Academic Search

    Henry U. Bryant; David L. Nelson; Donald Button; Harlan W. Cole; Melvyn B. Baez; Virginia L. Lucaites; David B. Wainscott; Cecilia Whitesitt; Jon Reel; Richard Simon; Gary A. Koppel

    1996-01-01

    Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding

  2. Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons

    Microsoft Academic Search

    Mayur Patil; Amol Patwardhan; Margaux M. Salas; Kenneth M. Hargreaves; Armen N. Akopian

    2011-01-01

    Cannabinoid receptor antagonists have been utilized extensively in vivo as well as in vitro, but their selectivity has not been fully examined. We investigated activation of sensory neurons by two cannabinoid antagonists – AM251 and AM630. AM251 and AM630 activated trigeminal (TG) sensory neurons in a concentration-dependent fashion (threshold 1?M). AM251 and AM630 responses are mediated by the TRPA1 channel in a

  3. Oxime derivatives related to AP18: Agonists and antagonists of the TRPA1 receptor

    Microsoft Academic Search

    Jeff DeFalco; Daniel Steiger; Amy Gustafson; Daniel E. Emerling; Michael G. Kelly; Matthew A. J. Duncton

    2010-01-01

    AP18 1 was recently disclosed as an antagonist of the TRPA1 receptor by the research group of Patapoutian. However, no detailed structure–activity relationships around 1 have been disclosed. Thus, a small number of oximes related to AP18 were examined in order to characterize the determinants of TRPA1 activity. Congeners of AP18 were found to possess both agonist and antagonist activity,

  4. Study of potency, kinetics of block and toxicity of NMDA receptor antagonists using fura-2

    Microsoft Academic Search

    Marsha Black; Thomas Lanthorn; Daniel Small; Geoffrey Mealing; Vincent Lam; Paul Morley

    1996-01-01

    NMDA receptor antagonists reduced NMDA-triggered increases in [Ca2+]i measured by fura-2 and showed qualitative differences in the potency and kinetics of block. High potency antagonists produced a slow block which allowed an initial increase in [Ca2+]i that was greater than the steady-state level, while compounds with moderate to low potency produced a rapid block that was at steady-state from the

  5. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept

    Microsoft Academic Search

    Daniel N. Cortright; Charles A. Blum; Samer R. Eid; Arpad Szallasi

    2007-01-01

    The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I\\/II clinical trials for the indications of chronic inflammatory pain and migraine.

  6. Design and evaluation of xanthine based adenosine receptor antagonists: Potential hypoxia targeted immunotherapies

    PubMed Central

    Thomas, Rhiannon; Lee, Joslynn; Chevalier, Vincent; Sadler, Sara; Selesniemi, Kaisa; Hatfield, Stephen; Sitkovsky, Michail; Ondrechen, Mary Jo; Jones, Graham B.

    2015-01-01

    Molecular modeling techniques were applied to the design, synthesis and optimization of a new series of xanthine based adenosine A2A receptor antagonists. The optimized lead compound was converted to a PEG derivative and a functional in vitro bioassay used to confirm efficacy. Additionally, the PEGylated version showed enhanced aqueous solubility and was inert to photoisomerization, a known limitation of existing antagonists of this class. PMID:24126093

  7. Analysis of Derivatives Subtypes Agonist and Antagonist Activities of Phenylglycine for Different Cloned Metabotropic Glutamate Receptor

    Microsoft Academic Search

    Yasunori Hayashi; Shigetada Nakanishi; David E. Jane; David C. Sunter; Ewan F. Birse; Peter M. Udvarhelyi; Jeffrey C. Watkins

    1994-01-01

    The metabotropic glutamate receptors (mGluRs) consist of at least seven different subtypes and are coupled to intra- cellular signal transduction via G proteins. However, the lack of specific antagonists for the mGluRs limited the precise characterization of the role of the individual mGluRs. In this study, we investigated the agonist and antagonist activities of a series of phenylglycine derivatives for

  8. Pharmacological, pharmacokinetic, and primate analgesic efficacy profile of the novel bradykinin B1 Receptor antagonist ELN441958.

    PubMed

    Hawkinson, Jon E; Szoke, Balazs G; Garofalo, Albert W; Hom, Dennis S; Zhang, Hongbing; Dreyer, Mark; Fukuda, Juri Y; Chen, Linda; Samant, Bhushan; Simmonds, Stellanie; Zeitz, Karla P; Wadsworth, Angie; Liao, Anna; Chavez, Raymond A; Zmolek, Wes; Ruslim, Lany; Bova, Michael P; Holcomb, Ryan; Butelman, Eduardo R; Ko, Mei-Chuan; Malmberg, Annika B

    2007-08-01

    The bradykinin B(1) receptor plays a critical role in chronic pain and inflammation, although efforts to demonstrate efficacy of receptor antagonists have been hampered by species-dependent potency differences, metabolic instability, and low oral exposure of current agents. The pharmacology, pharmacokinetics, and analgesic efficacy of the novel benzamide B(1) receptor antagonist 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecanecarbonyl)phenyl]-2,3-dihydro-isoindol-1-one (ELN441958) is described. ELN441958 competitively inhibited the binding of the B(1) agonist ligand [(3)H]desArg(10)-kallidin ([(3)H]DAKD) to IMR-90 human fibroblast membranes with high affinity (K(i) = 0.26 +/- 0.02 nM). ELN441958 potently antagonized DAKD (but not bradykinin)-induced calcium mobilization in IMR-90 cells, indicating that it is highly selective for B(1) over B(2) receptors. Antagonism of agonist-induced calcium responses at B(1) receptors from different species indicated that ELN441958 is selective for primate over rodent B(1) receptors with a rank order potency (K(B), nanomolar) of human (0.12 +/- 0.02) approximately rhesus monkey (0.24 +/- 0.01) > rat (1.5 +/- 0.4) > mouse (14 +/- 4). ELN441958 had good permeability and metabolic stability in vitro consistent with high oral exposure and moderate plasma half-lives in rats and rhesus monkeys. Because ELN441958 is up to 120-fold more potent at primate than at rodent B(1) receptors, it was evaluated in a primate pain model. ELN441958 dose-dependently reduced carrageenan-induced thermal hyperalgesia in a rhesus monkey tail-withdrawal model, with an ED(50) approximately 3 mg/kg s.c. Naltrexone had no effect on the antihyperalgesia produced by ELN441958, indicating a lack of involvement of opioid receptors. ELN441958 is a novel small molecule bradykinin B(1) receptor antagonist exhibiting high oral bioavailability and potent systemic efficacy in rhesus monkey inflammatory pain. PMID:17470643

  9. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer.

    PubMed

    Muñoz, Miguel; González-Ortega, Ana; Salinas-Martín, Manuel Vicente; Carranza, Andrés; Garcia-Recio, Susana; Almendro, Vanessa; Coveñas, Rafael

    2014-10-01

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in the development of cancer. No in-depth studies of the involvement of this system in breast cancer (BC) have been carried out, and the action exerted by the drug aprepitant on BC cells is currently unknown. We show the involvement of this system in human BC cell lines: i) these cells express mRNA for the NK-1 receptor; ii) they overexpress NK-1 receptors; iii) the NK-1 receptor is involved in their viability; iv) SP induces their proliferation; v) NK-1 receptor antagonists block SP-induced mitogen stimulation of these cells; vi) the specific antitumor action of such antagonists on these cells occurs through the NK-1 receptor; and vii) BC cell death is due to apoptosis. We also found NK-1 receptors and SP in all human BC samples studied. The NK-1 receptor may be a promising target in the treatment of BC and NK-1 receptor antagonists could be candidates as a new antitumor drug in the treatment of BC. PMID:25175857

  10. Combining the ?1-Adrenergic Receptor Antagonist, Prazosin, with the ?-Adrenergic Receptor Antagonist, Propranolol, Reduces Alcohol Drinking More Effectively Than Either Drug Alone

    PubMed Central

    Rasmussen, Dennis D; Beckwith, Lauren E; Kincaid, Carrie L; Froehlich, Janice C

    2014-01-01

    Background Evidence suggests that activation of the noradrenergic system may contribute to alcohol drinking in animals and humans. Our previous studies demonstrated that blocking ?1-adrenergic receptors with the antagonist, prazosin, decreased alcohol drinking in rats under various conditions. Since noradrenergic activation is also regulated by ?-adrenergic receptors, we now examine the effects of the ?-adrenergic receptor antagonist, propranolol, alone or in combination with prazosin, on alcohol drinking in rats selectively bred for high voluntary alcohol intake and alcohol preference (P line). Methods Two studies were conducted with male P rats. In study one, rats were allowed to become alcohol-dependent during 14 weeks of ad libitum access to food, water and 20% alcohol and the effect of propranolol (5–15 mg/kg, IP) and prazosin (1–2 mg/kg, IP) on alcohol intake during withdrawal were assessed. In study two, the effect of propranolol (5 mg/kg, IP) and prazosin (2 mg/kg, IP) on alcohol intake following prolonged imposed abstinence was assessed. Results Alcohol drinking following propranolol treatment was variable, but the combination of propranolol + prazosin consistently suppressed alcohol drinking during both alcohol withdrawal and following prolonged imposed abstinence, and the combination of these two drugs was more effective than was treatment with either drug alone. Conclusions Treatment with prazosin + propranolol, or a combination of other centrally active ?1- and ?-adrenergic receptor antagonists, may assist in preventing alcohol relapse in some individuals. PMID:24891220

  11. Further studies at neuropeptide S position 5: discovery of novel neuropeptide S receptor antagonists

    PubMed Central

    Guerrini, Remo; Camarda, Valeria; Trapella, Claudio; Calo’, Girolamo; Rizzi, Anna; Ruzza, Chiara; Fiorini, Stella; Marzola, Erika; Reinscheid, Rainer K.; Regoli, Domenico; Salvadori, Severo

    2009-01-01

    Neuropeptide S (NPS) regulates various biological functions by activating the NPS receptor (NPSR). Previous studies demonstrated that the substitution of Gly5 with D-amino acids generates NPSR antagonists. Eleven [D-Xaa5]NPS derivatives were synthesized and pharmacologically tested measuring [Ca2+]i in HEK293mNPSR cells. The present results confirmed that the [D-Xaa5] substitution promotes antagonist activity with potency inversely related to the side chain size and allowed to identify the novel potent NPSR peptide antagonist [tBu-D-Gly5]NPS. PMID:19473027

  12. Discriminative stimulus properties of cocaine: enhancement by beta-adrenergic receptor antagonists.

    PubMed

    Kleven, M S; Koek, W

    1997-06-01

    Although many of the behavioral effects of cocaine are widely believed to be mediated by blockade of dopamine transporters, recent studies suggest that norepinephrine (NE) may play a modulatory role. In this study, selective and nonselective beta-adrenergic receptor antagonists were administered alone or in combination with cocaine (2.5 mg/kg, i.p.) to rats trained to discriminate a low dose (2.5 mg/kg) from a high dose of cocaine (10 mg/kg) in a two-lever, FR10 drug discrimination procedure. The central beta 2/beta 1-adrenergic antagonists (-)-propranolol and tertatolol, and the beta 2-adrenergic antagonist, ICI 118,551, produced high-dose appropriate responding in a dose-related manner when administered (i.p.) in combination with the low training dose of cocaine. In contrast, neither the peripheral beta 2/beta 1-adrenergic antagonist, nadolol, nor the central beta 1-adrenergic antagonist, beta-xolol enhanced the behavioral effects of the low dose of cocaine in a manner comparable with that produced by compounds with central beta 2-adrenergic antagonist properties. Also in contrast to findings obtained using beta-adrenergic antagonists, neither the alpha 1-adrenergic agonist cirazoline, nor the alpha 2-adrenergic ligands (+/-)-efaroxan and UK-14304 enhanced the behavioral effects of the low dose of cocaine. Overall, these results suggest that central beta 2-adrenergic receptors may play a modulatory role in the discriminative stimulus effects of cocaine. PMID:9203242

  13. An Antagonistic Vascular Endothelial Growth Factor (VEGF) Variant Inhibits VEGF-Stimulated Receptor Autophosphorylation and Proliferation of Human Endothelial Cells

    NASA Astrophysics Data System (ADS)

    Siemeister, Gerhard; Schirner, Michael; Reusch, Petra; Barleon, Bernhard; Marme, Dieter; Martiny-Baron, Georg

    1998-04-01

    Vascular endothelial growth factor (VEGF) is a potent mitogen with a unique specificity for endothelial cells and a key mediator of aberrant endothelial cell proliferation and vascular permeability in a variety of human pathological situations, such as tumor angiogenesis, diabetic retinopathy, rheumatoid arthritis, or psoriasis. VEGF is a symmetric homodimeric molecule with two receptor binding interfaces lying on each pole of the molecule. Herein we report on the construction and recombinant expression of an asymmetric heterodimeric VEGF variant with an intact receptor binding interface at one pole and a mutant receptor binding interface at the second pole of the dimer. This VEGF variant binds to VEGF receptors but fails to induce receptor activation. In competition experiments, the heterodimeric VEGF variant antagonizes VEGF-stimulated receptor autophosphorylation and proliferation of endothelial cells. A 15-fold excess of the heterodimer was sufficient to inhibit VEGF-stimulated endothelial cell proliferation by 50%, and a 100-fold excess resulted in an almost complete inhibition. By using a rational approach that is based on the structure of VEGF, we have shown the feasibility to construct a VEGF variant that acts as an VEGF antagonist.

  14. GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology.

    PubMed

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels; Sørensen, Troels E; Krogsgaard-Larsen, Povl; Kristiansen, Uffe; Frølund, Bente

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown for only a few orthosteric ligands. Still, these examples show that it is indeed possible to obtain orthosteric subtype selectivity and they serve as models for further development in the orthosteric GABAAR ligand area. This review presents the very few existing structural classes of orthosteric GABAAR antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity. PMID:25600372

  15. Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor.

    PubMed

    Tokita, K; Katsuno, T; Hocart, S J; Coy, D H; Llinares, M; Martinez, J; Jensen, R T

    2001-09-28

    Few gastrointestinal hormones/neurotransmitters have high affinity peptide receptor antagonists, and little is known about the molecular basis of their selectivity or affinity. The receptor mediating the action of the mammalian bombesin (Bn) peptide, gastrin-releasing peptide receptor (GRPR), is an exception, because numerous classes of peptide antagonists are described. To investigate the molecular basis for their high affinity for the GRPR, two classes of peptide antagonists, a statine analogue, JMV594 ([d-Phe(6),Stat(13)]Bn(6-14)), and a pseudopeptide analogue, JMV641 (d-Phe-Gln-Trp-Ala-Val-Gly-His-Leupsi(CHOH-CH(2))-(CH(2))(2)-CH(3)), were studied. Each had high affinity for the GRPR and >3,000-fold selectivity for GRPR over the closely related neuromedin B receptor (NMBR). To investigate the basis for this, we used a chimeric receptor approach to make both GRPR loss of affinity and NMBR gain of affinity chimeras and a site-directed mutagenesis approach. Chimeric or mutated receptors were transiently expressed in Balb/c 3T3. Only substitution of the fourth extracellular (EC) domain of the GRPR by the comparable NMBR domain markedly decreased the affinity for both antagonists. Substituting the fourth EC domain of NMBR into the GRPR resulted in a 300-fold gain in affinity for JMV594 and an 11-fold gain for JMV641. Each of the 11 amino acid differences between the GRPR and NMBR in this domain were exchanged. The substitutions of Thr(297) in GRPR by Pro from the comparable position in NMBR, Phe(302) by Met, and Ser(305) by Thr decreased the affinity of each antagonist. Simultaneous replacement of Thr(297), Phe(302), and Ser(305) in GRPR by the three comparable NMBR amino acids caused a 500-fold decrease in affinity for both antagonists. Replacing the comparable three amino acids in NMBR by those from GRPR caused a gain in affinity for each antagonist. Receptor modeling showed that each of these three amino acids faced inward and was within 5 A of the putative binding pocket. These results demonstrate that differences in the fourth EC domain of the mammalian Bn receptors are responsible for the selectivity of these two peptide antagonists. They demonstrate that Thr(297), Phe(302), and Ser(305) of the fourth EC domain of GRPR are the critical residues for determining GRPR selectivity and suggest that both receptor-ligand cation-pi interactions and hydrogen bonding are important for their high affinity interaction. PMID:11463790

  16. LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor

    PubMed Central

    Pruneau, Didier; Luccarini, Jean-Michel; Fouchet, Chantal; Defrêne, Evelyne; Franck, Rose-Marie; Loillier, Bruno; Duclos, Hervé; Robert, Claude; Cremers, Béatrice; Bélichard, Pierre; Paquet, Jean-Luc

    1998-01-01

    In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-phenyl]sulphonyl]?-2(S)?-?[[4?-[4-(aminoiminomethyl)phenylcarbonyl]piperazin-1-yl]carbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B2 receptor.LF 16.0335 displaced [3H]-BK binding to membrane preparations from CHO cells expressing the cloned human B2 receptor, INT 407 cells and human umbilical vein with Ki values of 0.84±0.39?nM, 1.26±0.68?nM and 2.34±0.36?nM, respectively.In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, Bmax values of [3H]-BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist.LF 16.0335 had no affinity for the cloned human kinin B1 receptor stably expressed in 293 cells. In addition, this compound at 1??M did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M2 and M1 receptors for which an IC50 value of 0.9 and 1??M was obtained.BK stimulates in a concentration-dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration-response-curves to BK were shifted to the right in the presence of LF 16.0335 (0.1??M) without reduction of the maximum. LF 16.0335 inhibited the concentration-contraction curve to BK in the human umbilical vein giving a pA2 value of 8.30±0.30 with a Schild plot slope that was not different from unity.These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B2 receptor. PMID:9786510

  17. Sisters' curse: sexually antagonistic effects constrain the spread of a mitochondrial haplogroup superior in sperm competition.

    PubMed

    Padua, Michael V; Zeh, David W; Bonilla, Melvin M; Zeh, Jeanne A

    2014-12-22

    Maternal inheritance of mitochondria creates a sex-specific selective sieve with implications for male longevity, disease susceptibility and infertility. Because males are an evolutionary dead end for mitochondria, mitochondrial mutations that are harmful or beneficial to males but not females cannot respond directly to selection. Although the importance of this male/female asymmetry in evolutionary response depends on the extent to which mitochondrial mutations exert antagonistic effects on male and female fitness, few studies have documented sex-specific selection acting on mitochondria. Here, we exploited the discovery of two highly divergent mitochondrial haplogroups (A and B2) in central Panamanian populations of the pseudoscorpion Cordylochernes scorpioides. Next-generation sequencing and phylogenetic analyses suggest that selection on the ND4 and ND4L mitochondrial genes may partially explain sexually antagonistic mitochondrial effects on reproduction. Males carrying the rare B2 mitochondrial haplogroup enjoy a marked advantage in sperm competition, but B2 females are significantly less sexually receptive at second mating than A females. This reduced propensity for polyandry is likely to significantly reduce female lifetime reproductive success, thereby limiting the spread of the male beneficial B2 haplogroup. Our findings suggest that maternal inheritance of mitochondria and sexually antagonistic selection can constrain male adaptation and sexual selection in nature. PMID:25377452

  18. Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use.

    PubMed

    Merlo Pich, Emilio; Melotto, Sergio

    2014-01-01

    Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were initially associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA) suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders. In this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1) antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioral and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed. PMID:24592206

  19. Corticosteroid receptor antagonists are amnestic for passive avoidance learning in day-old chicks.

    PubMed

    Sandi, C; Rose, S P

    1994-08-01

    Glucocorticoids can modulate behavioural processes and neural plasticity. They are released during learning situations and can trigger neural actions through binding to brain receptors. We hypothesized that a glucocorticoid action could play a critical role in the mechanisms involved in long-term memory formation. In order to test this hypothesis, chicks were trained on a passive avoidance learning task and given bilateral intracerebral injections of selective mineralocorticoid (RU-28318) or glucocorticoid (RU-38486) receptor antagonists. The results showed that both antagonists alter information processing when injected prior to the training session. Possible state-dependent effects were discharged. Further experiments evaluating possible effects of the antagonists on concomitant aspects of the learning situation (such as novelty reaction and pecking pattern) indicated that, as opposed to the glucocorticoid receptor antagonist, the mineralocorticoid antagonist altered the birds' reactivity to non-specific aspects of the training task. These results suggest that the two types of intracellular corticosteroid receptors could be mediating different aspects of the information processing and storage involved in avoidance learning. In addition, this study points out that passive avoidance learning in the chick could be a good model to investigate the biochemical mechanisms involved in corticosteroid actions on learning-induced neural plasticity. PMID:7981871

  20. (-)Tertatolol is a potent antagonist at pre- and postsynaptic serotonin 5-HT1A receptors in the rat brain.

    PubMed

    Jolas, T; Haj-Dahmane, S; Lanfumey, L; Fattaccini, C M; Kidd, E J; Adrien, J; Gozlan, H; Guardiola-Lemaitre, B; Hamon, M

    1993-05-01

    The potential 5-HT1A antagonist properties of the beta-antagonist tertatolol were assessed using biochemical and electrophysiological assays in the rat. (+/-) Tertatolol bound with high affinity (Ki = 38 nM) to 5-HT1A sites labelled by [3H]8-OH-DPAT in hippocampal membranes. The (-)stereoisomer (Ki = 18 nM) was about 50-fold more potent than the (+)stereoisomer (Ki = 864 nM) to inhibit the specific binding of [3H]-8-OH-DPAT. As expected of a 5-HT1A antagonist, (-)tertatolol prevented in a concentration-dependent manner (Ki = 24 nM) the inhibitory effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates. Furthermore in vivo pretreatment with (-)tertatolol (5 mg/kg s.c.) significantly reduced the inhibitory influence of 8-OH-DPAT (0.3 mg/kg s.c.) on the accumulation of 5-hydroxytryptophan in various brain areas after the blockade of aromatic L-amino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in brainstem slices; Ki approximately 50 nM) and in vivo (in chloral hydrate anaesthetized rats; ID50 approximately 0.40 mg/kg i.v.), (-)tertatolol prevented the inhibitory effects of the 5-HT1A receptor agonists 8-OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninergic neurones within the dorsal raphe nucleus. In about 25% of these neurones, the basal firing rate was significantly increased by (-)tertatolol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the dorsal raphe nucleus)-and post (in the hippocampus)-synaptic 5-HT1A receptors in the rat brain. PMID:7686633

  1. Preparation and evaluation of 1,3-diaminocyclopentane-linked dihydropyrimidinone derivatives as selective ? 1a-receptor antagonists

    Microsoft Academic Search

    James C Barrow; Kristen L Glass; Harold G Selnick; Roger M Freidinger; Raymond S. L Chang; Stacey S O'Malley; Carla Woyden

    2000-01-01

    Several 1,3-diaminocyclopentane linked ?1a-receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their effect on ?1-receptor binding.

  2. Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.

    PubMed

    Geldenhuys, Werner J; Kuzenko, Stephanie R; Simmons, Mark A

    2010-11-25

    The NK(3) subtype of tachykinin receptor is a G protein-coupled receptor that is a potential therapeutic target for several neurological diseases, including schizophrenia. In this study, we have screened compound databases for novel NK(3) receptor antagonists using a virtual screening protocol of similarity analysis. The lead compound for this study was the potent NK(3) antagonist talnetant. Compounds of the quinoline type found in the virtual screen were additionally evaluated in a comparative molecular field analysis model to predict activity a priori to testing in vitro. Selected members of this latter set were tested for their ability to inhibit ligand binding to the NK(3) receptor as well as to inhibit senktide-induced calcium responses in cells expressing the human NK(3) receptor. Two novel compounds were identified that inhibited NK(3) receptor agonist binding, with potencies in the nM range and antagonized NK(3) receptor-mediated increases in intracellular calcium. These results demonstrate the utility of similarity analysis in identifying novel antagonist ligands for neuropeptide receptors. PMID:21047106

  3. Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist

    PubMed Central

    2010-01-01

    The structure?activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels. PMID:24900298

  4. Affinity of cholecystokinin receptor antagonists for the gastrin-binding protein

    Microsoft Academic Search

    Kristy A Rorison; Zhiyu Yang; Graham S Baldwin

    2000-01-01

    A 78 kDa gastrin-binding protein is a likely target for the anti-proliferative effects of the cholecystokinin (CCK) receptor antagonists d,l-4-benzamido-N,N-dipropylglutaramic acid (proglumide) and N-4-chlorobenzoyl-l-tryptophan (benzotript) on colorectal carcinoma cell lines [Baldwin, G.S., 1994. Antiproliferative gastrin\\/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein. Proc. Natl. Acad. Sci. USA 91, 7593–7597.]. Definition of the physiological role of the gastrin-binding protein has been

  5. Histamine H1 receptors on adherent rheumatoid synovial cells in culture: demonstration by radioligand binding and inhibition of histamine-stimulated prostaglandin E production by histamine H1 antagonists.

    PubMed Central

    Taylor, D J; Woolley, D E

    1987-01-01

    Histamine H1 receptors have been demonstrated on adherent rheumatoid synovial cells using biochemical and radioligand binding assays in vitro. The addition of histamine (17.8 mumol/l) to nine primary cultures of adherent rheumatoid synovial cells resulted in a two- to 21-fold increase in the production of prostaglandin E (PGE). This increase was inhibited by three H1 receptor antagonists (mepyramine, tripelennamine, and chlorpheniramine) in a dose related manner at concentrations below 10(-6) mol/l. Competitive binding assays with [3H]mepyramine gave ED50 values of approximately 10(-5) mol/l for the three H1 antagonists. H2 receptor antagonists (cimetidine and ranitidine) did not inhibit the histamine induced increase in PGE and did not compete effectively with the binding of H1 antagonists. PMID:2888437

  6. Competitive Androgen Receptor Antagonism as a Factor Determining the Predictability of Cumulative Antiandrogenic Effects of Widely Used Pesticides

    PubMed Central

    Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

    2012-01-01

    Background: Many pesticides in current use have recently been revealed as in vitro androgen receptor (AR) antagonists, but information about their combined effects is lacking. Objective: We investigated the combined effects and the competitive AR antagonism of pesticide mixtures. Methods: We used the MDA-kb2 assay to test a combination of eight AR antagonists that did not also possess AR agonist properties (“pure” antagonists; 8 mix: fludioxonil, fenhexamid, ortho-phenylphenol, imazalil, tebuconazole, dimethomorph, methiocarb, pirimiphos-methyl), a combination of five AR antagonists that also showed agonist activity (5 mix: cyprodinil, pyrimethanil, vinclozolin, chlorpropham, linuron), and all pesticides combined (13 mix). We used concentration addition (CA) and independent action (IA) to formulate additivity expectations, and Schild plot analyses to investigate competitive AR antagonism. Results: A good agreement between the effects of the mixture of eight “pure” AR antagonists and the responses predicted by CA was observed. Schild plot analysis revealed that the 8 mix acted by competitive AR antagonism. However, the observed responses of the 5 mix and the 13 mix fell within the “prediction window” boundaries defined by the predicted regression curves of CA and IA. Schild plot analysis with these mixtures yielded anomalous responses incompatible with competitive receptor antagonism. Conclusions: A mixture of widely used pesticides can, in a predictable manner, produce combined AR antagonist effects that exceed the responses elicited by the most potent component alone. Inasmuch as large populations are regularly exposed to mixtures of antiandrogenic pesticides, our results underline the need for considering combination effects for these substances in regulatory practice. PMID:23008280

  7. Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review.

    PubMed

    Vyas, V K; Ghate, M

    2010-12-01

    The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluid-electrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems. The RAS can be inhibited at various points to control pathogenesis of hypertension. Renin inhibitors and angiotensin-converting enzyme (ACE) inhibitors were the earliest RAS blocking agents. A relatively new class of compounds known as Ang II receptor antagonists (SARTANs) is developed for the treatment of hypertension. They exert their action by blocking the binding of Ang II on AT(1) receptor. Angiotensin converting enzyme (ACE) inhibitors are associated with incident of side effects such as cough and angioedema while clinical trials with Ang II receptor antagonists have confirmed that these drugs are safe and efficacious for the treatment of hypertension. Based upon the understanding of molecular interaction of Ang II receptor antagonists with AT(1) receptor some of the common structural features have been identified, such as a heterocyclic (nitrogen atom) ring system, an alkyl side chain and an acidic tetrazole group. Research efforts for development of new molecules with similar structural features have led to the discovery of various non-peptidic Ang II receptor antagonists with different substituted heterocyclic such as imidazole (losartan) and benzimidazole (candesartan and telmisartan). In this study we have critically reviewed various benzimidazole substituted compounds as Ang II-AT(1) receptor antagonists and explored other potential clinical uses for this class of compounds. PMID:20937029

  8. Identification of small molecule antagonists of the human mas-related gene-X1 receptor.

    PubMed

    Kunapuli, Priya; Lee, Seungtaek; Zheng, Wei; Alberts, Melissa; Kornienko, Oleg; Mull, Rebecca; Kreamer, Anthony; Hwang, Jong-Ik; Simon, Melvin I; Strulovici, Berta

    2006-04-01

    The recently identified mas-related-gene (MRG) family of receptors, located primarily in sensory neurons of the dorsal root ganglion, has been implicated in the perception of pain. Thus, antagonists of this class of receptors have been postulated to be useful analgesics. Toward this end, we developed a cell-based beta-lactamase (BLA) reporter gene assay to identify small molecule antagonists of the human MRG-X1 receptor from a library of compounds. Single-cell clones expressing functional receptors were selected using the BLA reporter gene technology. The EC50 for the MRG agonist peptide, BAM15, appeared to be comparable between the BLA assay and the intracellular Ca2+ transient assays in these cells. Ultra high-throughput screening of approximately 1 million compounds in a 1.8-microl cell-based BLA reporter gene assay was conducted in a 3456-well plate format. Compounds exhibiting potential antagonist profile in the BLA assay were confirmed in the second messenger Ca2+ transient assay. A cell-based receptor trafficking assay was used to further validate the mechanism of action of these compounds. Several classes of compounds, particularly the 2,3-disubstituted azabicyclo-octanes, appear to be relatively potent antagonists at the human MRG-X1 receptors, as confirmed by the receptor trafficking assay and radioligand binding studies. Furthermore, the structure-activity relationship reveals that within this class of compounds, the diphenylmethyl moiety is constant at the 2-substituent, whereas the 3-substituent is directly correlated with the antagonist activity of the compound. PMID:16510108

  9. A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

    PubMed Central

    Tolbert, W. David; Daugherty, Jennifer; Gao, ChongFeng; Xie, Qian; Miranti, Cindy; Gherardi, Ermanno; Vande Woude, George; Xu, H. Eric

    2007-01-01

    Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors. PMID:17804794

  10. Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance\\/dependence liability

    Microsoft Academic Search

    Stanley M Crain; Ke-Fei Shen

    2000-01-01

    Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism

  11. Discovery and development of orexin receptor antagonists as therapeutics for insomnia.

    PubMed

    Winrow, C J; Renger, J J

    2014-01-01

    Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for insomnia primarily target ?-aminobutyric acid-A (GABA-A) receptor signalling and include benzodiazepines and GABA-A receptor modulators. These drugs are used to address this sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance therapy. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the orexin receptors (single or dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual orexin receptors, while a number of DORAs have progressed to clinical development as pharmaceutical candidates for insomnia. The DORA almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with insomnia but its development was halted. SB-649868 and suvorexant have demonstrated efficacy and tolerability in Phase II and III trials respectively. Furthermore, suvorexant is currently under review by the Food and Drug Administration for the treatment of insomnia. Based on the publication of recent non-clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well-tolerated new class of medications for insomnia. PMID:23731216

  12. Proposed antagonists at GABAB receptors that inhibit adenylyl cyclase in cerebellar granule cell cultures of rat.

    PubMed

    Holopainen, I; Rau, C; Wojcik, W J

    1992-10-01

    The effects of various proposed GABAB receptor antagonists on baclofen-mediated inhibition of adenylyl cyclase were studied in cultured cerebellar granule cells from rat. (+/-)-Baclofen maximally inhibited adenylyl cyclase by approximately 60% of the basal enzyme activity with an EC50 value of 10 microM. 3-Aminopropane sulfonic acid (3-APS) and 5-aminovaleric acid (5-AVA) produced similar responses to that seen with (+/-)-baclofen. Saclofen reversed the action of (+/-)-baclofen, 50 microM, with a half maximal inhibitory concentration (IC50) of about 1.0 mM. The most effective antagonist in blocking the action of (+/-)-baclofen was 3-aminopropyl-diethoxy-methyl-phosphonic acid (CGP 35,348). In the presence of (+/-)-baclofen, 50 microM, the IC50 for CGP 35,348 was 290 microM and its inhibitory constant (KA) was 180 microM. The agonist-like actions of 3-APS and 5-AVA were antagonized by CGP 35,348 suggesting that 3-APS and 5-AVA may act as weak agonists at the GABAB receptor that inhibits adenylyl cyclase. All antagonists tested, except the new compound CGP 35,348, have very low potencies at GABAB receptors that inhibit adenylyl cyclase, though these compounds have been quite effective at other GABAB receptor-mediated events. Thus, the GABAB receptor which inhibits adenylyl cyclase differs pharmacologically from other reported GABAB receptor/effector systems and supports the existence of multiple receptor subtypes. PMID:1330652

  13. Identification of Trisubstituted-pyrazol Carboxamide Analogs as Novel and Potent Antagonists of Farnesoid X Receptor

    PubMed Central

    Yu, Donna D.; Lin, Wenwei; Forman, Barry M.; Chen, Taosheng

    2014-01-01

    Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR. PMID:24775917

  14. Angiotensin II receptor antagonists (AT1-blockers, ARBs, sartans): similarities and differences

    PubMed Central

    van Zwieten, P.A.

    2006-01-01

    A survey is presented of the registered non-peptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, telmisartan and valsartan. PMID:25696573

  15. The effects of NMDA receptor antagonists on attentional set-shifting task performance in mice

    Microsoft Academic Search

    Tomasz Kos; Agnieszka Nikiforuk; Dominik Rafa; Piotr Popik

    2011-01-01

    Rationale and objectives  Cognitive deficits, including an impaired ability to shift perceptual attentional set, belong to the core features of schizophrenia,\\u000a are associated with prefrontal cortical dysfunctions, and may involve glutamate NMDA receptors. Although phencyclidine disturbs\\u000a cognitive flexibility, little is known about the effects of ketamine and other NMDA antagonists that differ in receptor subunit\\u000a selectivity, particularly in the mouse species.

  16. GLUK1 receptor antagonists and hippocampal mossy fiber function.

    PubMed

    Nisticò, Robert; Dargan, Sheila; Fitzjohn, Stephen M; Lodge, David; Jane, David E; Collingridge, Graham L; Bortolotto, Zuner A

    2009-01-01

    Kainate receptors, one of the three subtypes of ionotropic receptors for the excitatory transmitter l-glutamate, play a variety of functions in the regulation of synaptic activity. Their physiological properties and functional roles have been identified only recently, following the discovery of selective pharmacological tools that allow for isolation of kainate receptor-mediated events. A considerable amount of data indicates that this class of glutamate receptors is located both at the pre- and postsynaptic site, playing a special role in regulating transmission and controlling short- and long-term plasticity. In this review, we summarize some data obtained in our laboratory over the last decade illustrating how various ligands have contributed to our understanding of the physiological role for neuronal kainate receptors. In particular, we show that the GluK1-containing KARs are important for regulating synaptic facilitation and LTP induction at hippocampal mossy fiber synapses. PMID:19607958

  17. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

    SciTech Connect

    Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya (Stanford-MED); (Kyoto); (Gakushuin); (Kyushu)

    2012-03-15

    The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

  18. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

    PubMed Central

    Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya

    2011-01-01

    The parasympathetic limb of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G protein coupled receptors (GPCRs) that mediate the response to acetylcholine released from parasympathetic nerves.1–5 Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiologic control of cardiovascular function through activation of G protein-coupled inwardly-rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of antagonist-bound M2 receptor, the first human acetylcholine receptor to be characterized structurally. The antagonist QNB binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all 5 muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The M2 receptor structure provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation. PMID:22278061

  19. Selective ? 1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones

    Microsoft Academic Search

    Philippe G Nantermet; James C Barrow; Harold G Selnick; Carl F Homnick; Roger M Freidinger; Raymond S. L Chang; Stacey S O'Malley; Duane R Reiss; Theodore P Broten; Richard W Ransom; Douglas J Pettibone; Timothy Olah; Carlos Forray

    2000-01-01

    A series of ?1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.

  20. Cyclic imides as potent and selective ?-1A adrenergic receptor antagonists

    Microsoft Academic Search

    Robert M DiPardo; Michael A Patane; Randall C Newton; RoseAnn Price; Theodore P Broten; Raymond S. L Chang; Richard W Ransom; Jerry Di Salvo; Roger M Freidinger; Mark G Bock

    2001-01-01

    We disclose a new compound class of potent and selective ?-1A adrenergic receptor antagonists exemplified by the geminally, disubstituted cyclic imide 7. The optimization of lead compounds resulting in the cyclic imide motif is highlighted. The results of in vitro and in vivo studies of selected compounds are presented.

  1. Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats

    Microsoft Academic Search

    Itsuro Kazama; Tomohiro Arata; Mari Michimata; Ryo Hatano; Michiko Suzuki; Noriyuki Miyama; Satoru Sanad; Akira Sato; Susumu Satomi; Yutaka Ejima; Sei Sasaki; Mitsunobu Matsubara

    2006-01-01

    Background. Although, pharmacological intervention with a selective arginine vasopressin (AVP) V2 receptor antagonist has been demonstrated to be effective for syndrome of inappropriate secretion of antidiuretic hormone (SIADH), its long-term administration has some therapeutic limitations. Lithium, a drug for bipolar disorders, has been known to cause nephro- genic diabetes insipidus by reducing kidney- specific apical water channel, aquaporin 2 (AQP2)

  2. I. Effects of a Dopamine Receptor Antagonist on Fathead Minnow, Pimephales promelas ,Reproduction

    EPA Science Inventory

    This study used a 21 d fathead minnow (Pimephales promelas) reproduction assay to test the hypothesis that exposure to the dopamine 2 receptor (D2R) antagonist, haloperidol, would impair fish reproduction. Additionally, a 96 h experiment with fathead minnows and zebrafish (Danio ...

  3. A Time-course Study with the Androgen Receptor Antagonist Flutamide in Fish

    EPA Science Inventory

    Flutamide, a drug registered to treat some types of prostate cancer in humans, has been used for many years as a model androgen receptor (AR) antagonist in studies aimed at characterizing disruption of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis. Various studies hav...

  4. Treatment of the overactive bladder syndrome with muscarinic receptor antagonists - a matter of metabolites?

    Microsoft Academic Search

    Martin C. Michel; Sharath S. Hegde

    2006-01-01

    Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the pharmacological activity of their metabolites and discuss how active metabolites may contribute to their efficacy and tolerability in vivo. Except for trospium, and

  5. The use of progesterone antagonists and progesterone receptor modulators in contraception

    Microsoft Academic Search

    Irving M Spitz; Paul F. A Van Look; Herjan J. T Coelingh Bennink

    2000-01-01

    Progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) have contraceptive potential by suppressing follicular development, delaying the surge of luteinizing hormone (LH), retarding endometrial maturation, and promoting endometrial bleeding. Mifepristone, in daily doses of 2–10 mg, blocks the LH surge and ovulation. Many of the studies were conducted in women not at risk of pregnancy, and thus the contraceptive efficacy

  6. Effect of some new H 2 -receptor antagonists on gastrointestinal motility

    Microsoft Academic Search

    G. Bertaccini; E. Poli; M. Adami; G. Coruzzi

    1983-01-01

    Some new histamine H2-receptor antagonists were tested for their effects on gastrointestinal motility. Ranitidine was found to possess definite stimulatory effects which appeared to be connected with an interference with the cholinergic system and occurred, though in different degree, from the lower esophageal sphincter (LES) to the colon. Etintidine, on the contrary, showed a remarkable antimuscarinic effect on the LES

  7. 3 -Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABAA Receptor Antagonists

    E-print Network

    Steinbach, Joe Henry

    3 -Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABAA Receptor Antagonists Mingde Wang,1 -hydroxypregnane steroids may com- petitively antagonize potentiation induced by their 3 diaste- reomers. Because -hydroxysteroids, 3 - hydroxysteroids acted noncompetitively with respect to potenti- ating steroids and inhibited

  8. III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.

    PubMed

    Kim, Seong Heon; Anilkumar, Gopinadhan N; Zawacki, Lisa Guise; Zeng, Qingbei; Yang, De-Yi; Shao, Yuefei; Dong, Guizhen; Xu, Xiaolian; Yu, Wensheng; Jiang, Yueheng; Jenh, Chung-Her; Hall, James W; Carroll, Carolyn Diianni; Hobbs, Doug W; Baldwin, John J; McGuinness, Brian F; Rosenblum, Stuart B; Kozlowski, Joseph A; Shankar, Bandarpalle B; Shih, Neng-Yang

    2011-12-01

    The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study. PMID:22018463

  9. Modeling binding equilibrium in a competitive estrogen receptor binding assay

    Microsoft Academic Search

    Jung-Hwan Kwon; Lynn E. Katz; Howard M. Liljestrand

    2007-01-01

    Although the free concentration is more significant in the environmental chemistry and toxicology of receptor-mediated toxicants, few studies have been conducted to use it as a dose-metric. The relative binding affinity of three model endocrine disrupting compounds, diethylstilbestrol (DES), ethynylestradiol (EE2), and bisphenol A (BPA), were evaluated using a competitive ELISA with human estrogen receptor ?. After measuring the available

  10. Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat.

    PubMed

    Dableh, Liliane J; Yashpal, Kiran; Rochford, Joseph; Henry, James L

    2005-01-10

    Although a wide assortment of agents is currently available for the treatment of depression, this disorder remains poorly managed in a large proportion of patients. Traditional antidepressant treatments target the biogenic amine systems. However, a growing body of evidence is implicating the involvement of neuropeptides in depression, especially the neurokinin substance P. This study evaluated the effects of selective antagonists of the tachykinin NK1, NK2, and NK3 receptors in the forced swim test, a commonly used screen for antidepressants. Rats were given CP-96,345 (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, or SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, antagonists of the NK1, NK2, and NK3 receptors, respectively, at doses of 2.5, 5, and 10 mg/kg, intraperitoneally (i.p.). The time of immobility during the forced swim test was used as an indicator of antidepressant activity of the antagonists. All antagonists decreased immobility times. CP-96,345 and SR 142801 showed dose-related effects; SR 48968 had its maximum effect at 2.5 mg/kg. The magnitude of the effects of the neurokinin receptor antagonists was approximately the same as that of amitriptyline and desipramine, two traditional antidepressants, both given at 10 mg/kg, i.p. This study provides comparative data on the relative effectiveness of NK1, NK2, and NK3 receptor antagonists in this screen for antidepressant drug activity. PMID:15659299

  11. ( sup 3 H)SCH39166, a D1 dopamine receptor antagonist: Binding characteristics and localization

    SciTech Connect

    Wamsley, J.K.; Hunt, M.E.; McQuade, R.D.; Alburges, M.E. (Neuropsychiatric Research Institute, Fargo, ND (USA))

    1991-02-01

    Schering-Plough Research has developed a new, more specific analogue of SCH23390. This compound, SCH39166, has been shown to be a potent, specific, D1 receptor antagonist with several features which are advantageous over its predecessor. In this report, the binding characteristics of (3H)SCH39166 are described by in vitro analysis in rat brain tissues. The binding was shown to be of high affinity (Kd in the low nM range), saturable, and specific (readily displaceable with SCH23390, but not with the D2 receptor antagonists sulpiride or haloperidol). The binding of SCH39166 is more selective for binding to D1 receptors than SCH23390 with regard to overlap of the latter compound onto 5HT2 and 5HT1C receptors. Autoradiographic localization of D1 receptor sites labeled with (3H)SCH39166 showed a very specific distribution in areas known to contain high quantities of D1 receptors. These regions included the deepest layer of the cerebral cortex, the caudate-putamen, nucleus accumbens, olfactory tubercle, entopeduncular nucleus, and substantia nigra-pars reticulata, as well as less dense binding in a few other areas. At the concentration of ligand used (1 nM), there was a noticeable paucity of labeling in lamina IV of the cerebral cortex and in the choroid plexus, regions of high 5HT2 and 5HT1C receptor binding, respectively. Thus, SCH39166 represents a new D1 receptor antagonist which shows a greater specificity for the D1 receptor than its predecessor SCH23390. As previously shown, another distinct advantage of this compound is its stability in primates which should allow the determination of the effects and utility of D1 receptor antagonism in vivo.

  12. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate.

    PubMed

    Di Fabio, Romano; Alvaro, Giuseppe; Braggio, Simone; Carletti, Renzo; Gerrard, Philip A; Griffante, Cristiana; Marchioro, Carla; Pozzan, Alfonso; Melotto, Sergio; Poffe, Alessandro; Piccoli, Laura; Ratti, Emiliangelo; Tranquillini, Elvira; Trower, Michael; Spada, Simone; Corsi, Mauro

    2013-11-01

    The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties. PMID:24075145

  13. Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders

    PubMed Central

    Heidbreder, Christian A.; Newman, Amy H.

    2011-01-01

    Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed. PMID:20201845

  14. New bicyclic cannabinoid receptor-1 (CB 1-R) antagonists

    Microsoft Academic Search

    Philip A. Carpino; David A. Griffith; Subas Sakya; Robert L. Dow; Shawn C. Black; John R. Hadcock; Philip A. Iredale; Dennis O. Scott; Michael W. Fichtner; Colin R. Rose; Robert Day; Joseph Dibrino; Mary Butler; Demetria B. DeBartolo; Darrin Dutcher; Denise Gautreau; Jeff S. Lizano; Rebecca E. O’Connor; Michelle A. Sands; Dawn Kelly-Sullivan; Karen M. Ward

    2006-01-01

    A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB1-R antagonists and inverse agonists. Optimization of the structure–activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in

  15. Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.

    PubMed Central

    Halmos, G; Schally, A V; Pinski, J; Vadillo-Buenfil, M; Groot, K

    1996-01-01

    Antagonists of luteinizing hormone-releasing hormone (LH-RH), unlike the LH-RH agonists, suppress gonadotropins and sex steroid secretion immediately after administration, without initial stimulatory effects. [Ac-D-Nal(2)1,D-Ph(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-R H (SB-75; Cetrorelix) is a modern, potent antagonistic analog of LH-RH. In this study, the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries were investigated after a single injection of Cetrorelix at a dose of 100 microg per rat. To determine whether the treatment with Cetrorelix can affect the concentration of measurable LH-RH binding sites, we applied an in vitro method to desaturate LH-RH receptors by chaotropic agents such as manganous chloride (MnCl2) and ammonium thiocyanate (NH4SCN). Our results show that the percentages of occupied LH-RH receptors at 1, 3, and 6 h after administration of Cetrorelix were approximately 28%, 14%, and 10%, respectively, of total receptors. At later time intervals, we could not detect occupied LH-RH binding sites. Ligand competition assays, following in vitro desaturation, demonstrated that rat pituitary LH-RH receptors were significantly (P < 0.01) down-regulated for at least 72 h after administration of Cetrorelix. The lowest receptor concentration was found 3-6 h after Cetrorelix treatment and a recovery in receptor number began within approximately 24 h. The down-regulation of LH-RH binding sites induced by Cetrorelix was accompanied by serum LH and testosterone suppression. Higher LH-RH receptor concentrations coincided with elevated serum hormone levels at later time intervals. Our results indicate that administration of LH-RH antagonist Cetrorelix produces a marked down-regulation of pituitary receptors for LH-RH and not merely an occupancy of binding sites. PMID:8637885

  16. Malonamic acid derivatives as M1 selective muscarinic receptor antagonists.

    PubMed

    Turconi, M; Banfi, A; Schiavi, G B; Donetti, A

    1991-09-01

    A series of malonamic acid esters with suitable amino alcohols, typical of antimuscarinic compounds, was synthesized and the affinities for the three pharmacologically defined muscarinic receptor subtypes, namely M1, M2 and M3, were evaluated by radioligand displacement experiments. It was found that the esters with 3-quinuclidinol 7b, 7f-g, 8 and 9 are ligands with intermediate to high affinity for the M1 receptors, for which they show a preferential binding. Unexpectedly, the ester 7a with tropine bound with negligible affinity to all the receptors investigated. The introduction of a phenyl group on the carboxamido moiety of 7b gave compound 9, which showed an affinity for the M1 receptor comparable with that of the reference drug Pirenzepine 1. PMID:1807294

  17. Inverse antagonist activities of parabens on human oestrogen-related receptor ? (ERR?): In vitro and in silico studies

    SciTech Connect

    Zhang, Zhaobin; Sun, Libei; Hu, Ying; Jiao, Jian; Hu, Jianying, E-mail: hujy@urban.pku.edu.cn

    2013-07-01

    Parabens are p-hydroxybenzoic acid esters that have been used extensively as preservatives in foods, cosmetics, drugs and toiletries. These intact esters are commonly detected in human breast cancer tissues and other human samples, thus arousing concern about the involvement of parabens in human breast cancer. In this study, an in vitro nuclear receptor coactivator recruiting assay was developed and used to evaluate the binding activities of parabens, salicylates and benzoates via antagonist competitive binding on the human oestrogen-related receptor ? (ERR?), which is known as both a diagnostic biomarker and a treatment target of breast cancer. The results showed that all of the test parabens (methyl-, ethyl-, propyl-, butyl- and benzylparaben) possessed clear inverse antagonist activities on ERR?, with a lowest observed effect level (LOEL) of 10{sup ?7} M and the 50% relative effective concentrations (REC50) varying from 3.09 × 10{sup ?7} to 5.88 × 10{sup ?7} M, whereas the salicylates possessed much lower activities and the benzoates showed no obvious activity. In silico molecular docking analyses showed that parabens fitted well into the active site of ERR?, with hydrogen bonds forming between the p-hydroxyl group of parabens and the Glu275/Arg316 of ERR?. As the paraben levels reported in breast cancer tissues are commonly higher than the LOELs observed in this study, parabens may play some role via ERR? in the carcinogenesis of human breast cancer. In addition, parabens may have significant effects on breast cancer patients who are taking tamoxifen, as ERR? is regarded as a treatment target for tamoxifen. - Highlights: • An oestrogen-related receptor ? coactivator recruiting assay was developed. • Strong binding activities of parabens with oestrogen-related receptor ? were found. • The paraben levels reported in breast cancer tissues were higher than their LOELs. • Parabens may play some role via ERR? in the carcinogenesis of human breast cancer. • Parabens may have significant effects in breast cancer patients taking tamoxifen.

  18. A prototypical Sigma1 receptor antagonist protects against brain ischemia

    Microsoft Academic Search

    John A. Schetz; Evelyn Perez; Ran Liu; Shiuhwei Chen; Ivan Lee; James W. Simpkins

    2007-01-01

    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

  19. Identification and enzymatic deglycosylation of the myometrial oxytocin receptor using a radioiodinated photoreactive antagonist.

    PubMed

    Kojro, E; Hackenberg, M; Zsigo, J; Fahrenholz, F

    1991-11-15

    To identify and characterize oxytocin receptors, a 125I-labeled photoreactive oxytocin antagonist was synthesized. The specific oxytocin antagonist [1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid), 2-O-methyltyrosine,4-threonine,8- ornithine,9-tyrosylamide]oxytocin ([Mca,Tyr(O-Me)2,Thr4,Orn8,Tyr9-NH2]oxytocin) described by Elands et al. (Elands, J., Barberis, C., Jard, S., Tribollet, E., Dreifuss, J.-J., Bankowski, K., Manning, M., and Sawyer, W. H. (1987) Eur. J. Pharmacol. 147, 192-207) bound to the guinea pig uterine oxytocin receptor with high affinity (apparent Kd = 0.74 nM). The introduction of a 4-azidophenylamidino group at Orn8 resulted in the photoreactive ligand [Mca1,Tyr(O-Me)2,Thr4,Orn(4-azidophenylamidino)8,Tyr9- NH2]oxytocin, which retained the high binding affinity (Kd = 0.69 nM) of the parent compound. The photoreactive antagonist monoiodinated at Tyr9 had approximately double (Kd = 0.39 nM) the affinity of the photoreactive antagonist and several times that of oxytocin (Kd = 2.6 nM) for the guinea pig uterine oxytocin receptor. In photo-affinity labeling experiments using myometrial membranes obtained from guinea pigs during late pregnancy, the 125I-labeled photoreactive antagonist specifically labeled a protein with an apparent molecular mass of between 68 and 80 kDa: the labeling of this protein was completely suppressed by a 100-fold molar excess of oxytocin and oxytocin receptor-specific agonists, but not by vasopressin analogues specific for V1 or V2 receptors or by other peptide hormones. The ability of oxytocin to suppress labeling was decreased in the presence of guanosine 5'-O-(thiotriphosphate) or in the absence of Mn2+. Digestion of the photolabeled oxytocin receptor with endoglycosidase F gave rise to a protein with an apparent molecular mass of 38 +/- 2 kDa. The endoglycosidase F effect and the lack of endoglycosidase H action show that the myometrial oxytocin receptor is highly glycosylated with asparagine-linked complex oligosaccharide chains. Our results suggest that the radioiodinated photoreactive oxytocin antagonist could be a helpful tool in the isolation and further characterization of the oxytocin receptor. PMID:1657965

  20. Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists.

    PubMed

    Selfridge, Brandon R; Wang, Xiaohui; Zhang, Yingning; Yin, Hang; Grace, Peter M; Watkins, Linda R; Jacobson, Arthur E; Rice, Kenner C

    2015-06-25

    Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N-phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 1j) showed ?75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 ?M/1.4 ?M) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia. PMID:26010811

  1. Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A3 Adenosine Receptors

    PubMed Central

    Li, An-Hu; Chang, Louis; Ji, Xiao-duo; Melman, Neli; Jacobson, Kenneth A.

    2012-01-01

    4-Phenylethynyl-6-phenyl-1,4-dihydropyridine derivatives are selective antagonists at human A3 adenosine receptors, with Ki values in a radioligand binding assay vs [125I]AB-MECA [N6-(4-amino-3-iodobenzyl)-5?-N-methylcarbamoyl-adenosine] in the submicromolar range. In this study, functionalized congeners of 1,4-dihydropyridines were designed as chemically reactive adenosine A3 antagonists, for the purpose of synthesizing molecular probes for this receptor subtype. Selectivity of the new analogues for cloned human A3 adenosine receptors was determined in radioligand binding in comparison to binding at rat brain A1 and A2A receptors. Benzyl ester groups at the 3- and/or 5-positions and phenyl groups at the 2- and/or 6-positions were introduced as potential sites for chain attachment. Structure–activity analysis at A3 adenosine receptors indicated that 3,5-dibenzyl esters, but not 2,6-diphenyl groups, are tolerated in binding. Ring substitution of the 5-benzyl ester with a 4-fluorosulfonyl group provided enhanced A3 receptor affinity resulting in a Ki value of 2.42 nM; however, a long-chain derivative containing terminal amine functionalization at the 4-position of the 5-benzyl ester showed only moderate affinity. This sulfonyl fluoride derivative appeared to bind irreversibly to the human A3 receptor (1 h incubation at 100 nM resulting in the loss of 56% of the specific radioligand binding sites), while the binding of other potent dihydropyridines and other antagonists was generally reversible. At the 3-position of the dihydropyridine ring, an amine-functionalized chain attached at the 4-position of a benzyl ester provided higher A3 receptor affinity than the corresponding 5-position isomer. This amine congener was also used as an intermediate in the synthesis of a biotin conjugate, which bound to A3 receptors with a Ki value of 0.60 ?M. PMID:10411465

  2. The antiproliferative action of [D-Arg(1), D-Phe(5), D-Trp(7,9), LEU(11)] substance P analogue antagonist against small-cell- and non-small-cell lung cancer cells could be due to the pharmacological profile of its tachykinin receptor antagonist.

    PubMed

    Munoz, M; Recio, S; Rosso, M; Redondo, M; Covenas, R

    2015-06-01

    It is known that in human lung cancer samples, both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cells express the neurokinin-1 (NK-1) receptor; that after binding to the NK-1 receptor the peptide substance P (SP) elicits tumour cell proliferation and an antiapoptotic effect. By contrast, it has been demonstrated that non-peptide NK-1 receptor antagonists, after binding to the NK-1 receptor and hence by blocking the SP action in SCLC/NSCLC, exert an antiproliferative action (inhibit lung cancer cell proliferation and induce the death of tumour cells by apoptosis). It is also known that SP peptide NK-1 receptor antagonists also called SP analogue antagonists (broad-spectrum GPCR antagonists, broad-spectrum neuropeptide antagonists or synthetic analogues of SP), also exert antiproliferative actions against SCLC/NSCLC. However, the underlying mechanisms involved in this antiproliferative action remain unknown. By using competition assays with SP, here we demonstrate that the antiproliferative action exerted by the [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)] SP analogue on human H-69 SCLC and COR-L23 NSCLC cell lines, occurs at least through the NK-1 receptor. PMID:26084224

  3. Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist.

    PubMed

    Winrow, Christopher J; Gotter, Anthony L; Cox, Christopher D; Doran, Scott M; Tannenbaum, Pamela L; Breslin, Michael J; Garson, Susan L; Fox, Steven V; Harrell, Charles M; Stevens, Joanne; Reiss, Duane R; Cui, Donghui; Coleman, Paul J; Renger, John J

    2011-03-01

    Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 ?M. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia. PMID:21473737

  4. Analgesic effects of morphine and loperamide in the rat formalin test: interactions with NMDA receptor antagonists.

    PubMed

    Sevostianova, Natalja; Danysz, Wojciech; Bespalov, Anton Y

    2005-11-21

    To reveal peripheral components of opiate analgesia, effects of loperamide, opioid agonist which does not penetrate the blood-brain barrier, were examined in formalin and acute thermal pain tests in comparison with morphine. Formalin administration induces pain behaviour such licking/biting of injected paw expressed as two phases. The first phase is caused by C-fibre activation due to peripheral stimulation, the second phase attributed to ongoing input from peripheral site, leading to spinal hyperexcitability, which is dependent on N-methyl-D-aspartate (NMDA) receptor activation. Loperamide (3-10 mg/kg) and morphine (6 mg/kg) reduced formalin-induced nociceptive behaviours and these effects were reversed by naloxone methiodide (0.03-10 mg/kg), opioid receptor antagonist which poorly penetrates the blood-brain barrier. Loperamide action was enhanced only by centrally active NMDA receptor antagonists memantine (3 mg/kg) and CGP 37849 (3 mg/kg), but not by NMDA/glycineB receptor antagonists showing weak or no central nervous system (CNS) activity. Present results suggest that central NMDA receptor blockade may be necessary to enhance analgesia induced through peripheral opioid mechanisms in formalin-evoked nociception. PMID:16297905

  5. Properties of a new radioiodinated antagonist for human vasopressin V2 and V1a receptors.

    PubMed

    Ala, Y; Morin, D; Mahé, E; Cotte, N; Mouillac, B; Jard, S; Barberis, C; Tribollet, E; Dreifuss, J J; Sawyer, W H; Wo, N C; Chan, W Y; Kolodziejczyk, A S; Cheng, L L; Manning, M

    1997-07-23

    A vasopressin receptor antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid), 2-o-ethyl-D-tyrosine, 4-valine, 9-tyrosylamide] arginine vasopressin (d(CH2)5[o-ethyl-D-Tyr2,Val4,Tyr-NH9(2)]AVP), has been prepared. This antagonist is a potent antiantidiuretic, antivasopressor and antioxytocic peptide with pA2 values of 7.69-7.94 and affinities of 1.12-11.0 nM. When radioiodinated at the phenyl moiety of the tyrosylamide residue at position 9, this peptide was demonstrated to bind to vasopressin V2 and V1a receptors with a dissociation constant of 0.22-0.75 nM. This ligand is a good tool for further studies on human vasopressin V2 receptor localization and characterization, when used in combination with a selective vasopressin V1a ligand. PMID:9274991

  6. Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1*

    PubMed Central

    Benod, Cindy; Carlsson, Jens; Uthayaruban, Rubatharshini; Hwang, Peter; Irwin, John J.; Doak, Allison K.; Shoichet, Brian K.; Sablin, Elena P.; Fletterick, Robert J.

    2013-01-01

    Liver receptor homolog 1 (nuclear receptor LRH-1, NR5A2) is an essential regulator of gene transcription, critical for maintenance of cell pluripotency in early development and imperative for the proper functions of the liver, pancreas, and intestines during the adult life. Although physiological hormones of LRH-1 have not yet been identified, crystallographic and biochemical studies demonstrated that LRH-1 could bind regulatory ligands and suggested phosphatidylinositols as potential hormone candidates for this receptor. No synthetic antagonists of LRH-1 are known to date. Here, we identify the first small molecule antagonists of LRH-1 activity. Our search for LRH-1 modulators was empowered by screening of 5.2 million commercially available compounds via molecular docking followed by verification of the top-ranked molecules using in vitro direct binding and transcriptional assays. Experimental evaluation of the predicted ligands identified two compounds that inhibit the transcriptional activity of LRH-1 and diminish the expression of the receptor's target genes. Among the affected transcriptional targets are co-repressor SHP (small heterodimer partner) as well as cyclin E1 (CCNE1) and G0S2 genes that are known to regulate cell growth and proliferation. Treatments of human pancreatic (AsPC-1), colon (HT29), and breast adenocarcinoma cells T47D and MDA-MB-468 with the LRH-1 antagonists resulted in the receptor-mediated inhibition of cancer cell proliferation. Our data suggest that specific antagonists of LRH-1 could be used as specific molecular probes for elucidating the roles of the receptor in different types of malignancies. PMID:23667258

  7. Structure-based discovery of antagonists of nuclear receptor LRH-1.

    PubMed

    Benod, Cindy; Carlsson, Jens; Uthayaruban, Rubatharshini; Hwang, Peter; Irwin, John J; Doak, Allison K; Shoichet, Brian K; Sablin, Elena P; Fletterick, Robert J

    2013-07-01

    Liver receptor homolog 1 (nuclear receptor LRH-1, NR5A2) is an essential regulator of gene transcription, critical for maintenance of cell pluripotency in early development and imperative for the proper functions of the liver, pancreas, and intestines during the adult life. Although physiological hormones of LRH-1 have not yet been identified, crystallographic and biochemical studies demonstrated that LRH-1 could bind regulatory ligands and suggested phosphatidylinositols as potential hormone candidates for this receptor. No synthetic antagonists of LRH-1 are known to date. Here, we identify the first small molecule antagonists of LRH-1 activity. Our search for LRH-1 modulators was empowered by screening of 5.2 million commercially available compounds via molecular docking followed by verification of the top-ranked molecules using in vitro direct binding and transcriptional assays. Experimental evaluation of the predicted ligands identified two compounds that inhibit the transcriptional activity of LRH-1 and diminish the expression of the receptor's target genes. Among the affected transcriptional targets are co-repressor SHP (small heterodimer partner) as well as cyclin E1 (CCNE1) and G0S2 genes that are known to regulate cell growth and proliferation. Treatments of human pancreatic (AsPC-1), colon (HT29), and breast adenocarcinoma cells T47D and MDA-MB-468 with the LRH-1 antagonists resulted in the receptor-mediated inhibition of cancer cell proliferation. Our data suggest that specific antagonists of LRH-1 could be used as specific molecular probes for elucidating the roles of the receptor in different types of malignancies. PMID:23667258

  8. Receptor-specific activity of heteromeric thyrotropin (TSH) analogs: development of synthetic TSH antagonists.

    PubMed

    Sheehan, M T; Morbeck, D E; Bergert, E R; McCormick, D J; Milius, R P; Morris, J C

    1995-01-01

    In an attempt to create potent and specific inhibitors of the interaction of thyrotropin (thyroid-stimulating hormone [TSH]) with its receptor, we designed a series of 18 synthetic peptides containing sequences of both alpha and beta subunits that were shown previously to interact with the TSH receptor. These "heteromeric" peptide analogs included amino acid residues from alpha 26-46, beta 31-52, beta 88-95 and beta 101-112 that were arranged variously and were separated from each other by artificial amino acid spacers. Each peptide was tested for its ability to interact with the TSH receptor in a radio-receptor assay (TSH-RRA) using porcine thyroid membranes and a bio-assay for TSH using FRTL-5 cells. Twelve of the 18 peptides showed binding activity in the TSH-RRA. None of the analogs demonstrated thyroid stimulatory activity, but five inhibited TSH bioactivity and were, thus, pure antagonists, the most potent possessing EC50 values in the 3-5 microM range. Specificity of the antagonists was tested by measuring their ability to inhibit hCG binding to ovarian membranes, hCG-stimulated progesterone production in MA-10 rat Leydig tumor cells and FSH binding to testicular membranes. Only those peptides that included the alpha-subunit sequence CFSR or CCFSR exhibited binding activity for the heterologous receptors, and that activity was 10-fold lower than in the TSH assays. None of the heteromeric peptides showed activity in the hCG bioassays, further demonstrating their specificity as TSH antagonists. These studies illustrate the utility of a synthetic peptide approach in the development of analogs of peptide hormones. Future alterations that significantly enhance the potency of these antagonists may result in substances with clinical efficacy in diseases such as Graves' disease and differentiated thyroid cancer that involve the thyrotropin receptor. PMID:8589548

  9. Sigma 1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice

    Microsoft Academic Search

    J. Kitanaka; N. Kitanaka; T. Tatsuta; F. S. Hall; G. R. Uhl; K. Tanaka; N. Nishiyama; Y. Morita; M. Takemura

    2009-01-01

    Objective  The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined\\u000a the effects of sigma antagonists on METH-induced stereotypy in mice.\\u000a \\u000a \\u000a \\u000a Results  The administration of METH (10 mg\\/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.1%), sniffing\\u000a (4.2%), head bobbing (4.1%), and circling (1.7%) during an observation period of 1 h. Pretreatment of the mice

  10. Antagonists of Metabotropic Glutamate Receptors Prevent the Development of Audiogenic Seizures.

    PubMed

    Bashkatova, V G; Sudakov, S K; Prast, H

    2015-05-01

    Pretreatment with mGluR1 antagonist AIDA (1 mg/kg) nearly completely prevented the onset of tonic-clonic seizures and increased generation of NO in the cerebral cortex of rats with genetically determined audiogenic reaction to acoustic stimulation. Administration of mGluR5 antagonist MPEP (10 mg/kg) before audiogenic exposure was followed by a significant decrease in the degree of seizure and partially prevented increased generation of NO due to acoustic stimulation. These data indicate that mGlu receptors and NO play an important role in the pathogenetic mechanisms of audiogenic seizures. PMID:26033576

  11. Benzodiazepine receptor antagonists modulate the actions of ethanol in alcohol-preferring and -nonpreferring rats

    Microsoft Academic Search

    Harry L June; Samantha L Devaraju; Mary W Eggers; John A Williams; Charity R Cason; Terri L Greene; Trevlyn Leveige; Misty R Braun; Lucas Torres; James M Murphy

    1998-01-01

    The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5H)-one, 0.05-2 mg\\/kg) and the ?-carboline ZK 93426 (ethyl-5-isopropyl-4-methyl-?-carboline-3-carboxylate, 1–10 mg\\/kg) benzodiazepine receptor antagonists were evaluated for their capacity to modulate the behavioral actions of ethanol in alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were presented with a two-bottle choice test between ethanol (10% v\\/v) and a saccharin (0.0125% g\\/v) solution, both antagonists dose-dependently

  12. Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

    PubMed

    Serradeil-Le Gal, C; Lacour, C; Valette, G; Garcia, G; Foulon, L; Galindo, G; Bankir, L; Pouzet, B; Guillon, G; Barberis, C; Chicot, D; Jard, S; Vilain, P; Garcia, C; Marty, E; Raufaste, D; Brossard, G; Nisato, D; Maffrand, J P; Le Fur, G

    1996-12-15

    SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases. PMID:8981918

  13. Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

    PubMed Central

    Serradeil-Le Gal, C; Lacour, C; Valette, G; Garcia, G; Foulon, L; Galindo, G; Bankir, L; Pouzet, B; Guillon, G; Barberis, C; Chicot, D; Jard, S; Vilain, P; Garcia, C; Marty, E; Raufaste, D; Brossard, G; Nisato, D; Maffrand, J P; Le Fur, G

    1996-01-01

    SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases. PMID:8981918

  14. RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist

    PubMed Central

    Bonhaus, Douglas W; Flippin, Lee A; Greenhouse, Robert J; Jaime, Saul; Rocha, Cindy; Dawson, Mark; Van Natta, Kristine; Chang, L K; Pulido-Rios, Tess; Webber, Andrea; Leung, Edward; Eglen, Richard M; Martin, Graeme R

    1999-01-01

    Efforts to define precisely the role of 5-HT2B receptors in normal and disease processes have been hindered by the absence of selective antagonists. To address this deficiency, we developed a series of naphthylpyrimidines as potentially useful 5-HT2B receptor antagonists. RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine) was found to have nanomolar affinity for the 5-HT2B receptor (pKi=9.5±0.1) and 1,000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites. In cells expressing human recombinant 5-HT2B receptors, RS-127445 potently antagonized 5-HT-evoked formation of inositol phosphates (pKB=9.5±0.1) and 5-HT-evoked increases in intracellular calcium (pIC50=10.4±0.1). RS-127445 also blocked 5-HT-evoked contraction of rat isolated stomach fundus (pA2=9.5±1.1) and (±)?-methyl-5-HT-mediated relaxation of the rat jugular vein (pA2=9.9±0.3). RS-127445 had no detectable intrinsic activity in these assays. In rats, the fraction of RS-127445 that was bioavailable via the oral or intraperitoneal routes was 14 and 60% respectively. Intraperitoneal administration of RS-127445 (5?mg?kg?1) produced plasma concentrations predicted to fully saturate accessible 5-HT2B receptors for at least 4?h. In conclusion, RS-127445 is a selective, high affinity 5-HT2B receptor antagonist suitable for use in vivo. The therapeutic potential of this molecule is being further evaluated. PMID:10455251

  15. Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists.

    PubMed

    Ronconi, Vanessa; Turchi, Federica; Appolloni, Gloria; di Tizio, Valentina; Boscaro, Marco; Giacchetti, Gilberta

    2012-03-01

    Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosterone independent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium- dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae. PMID:22022770

  16. Molecular determinants for competitive inhibition of alpha4beta2 nicotinic acetylcholine receptors.

    PubMed

    Iturriaga-Vásquez, Patricio; Carbone, Annalisa; García-Beltrán, Olimpo; Livingstone, Phil D; Biggin, Philip C; Cassels, Bruce K; Wonnacott, Susan; Zapata-Torres, Gerald; Bermudez, Isabel

    2010-09-01

    The Erythrina alkaloids erysodine and dihydro-beta-erythroidine (DHbetaE) are potent and selective competitive inhibitors of alpha4beta2 nicotinic acetylcholine receptors (nAChRs), but little is known about the molecular determinants of the sensitivity of this receptor subtype to inhibition by this class of antagonists. We addressed this issue by examining the effects of DHbetaE and a range of aromatic Erythrina alkaloids on [(3)H]cytisine binding and receptor function in conjunction with homology models of the alpha4beta2 nAChR, mutagenesis, and functional assays. The lactone group of DHbetaE and a hydroxyl group at position C-16 in aromatic Erythrina alkaloids were identified as major determinants of potency, which was decreased when the conserved residue Tyr126 in loop A of the alpha4 subunit was substituted by alanine. Sensitivity to inhibition was also decreased by substituting the conserved aromatic residues alpha4Trp182 (loop B), alpha4Tyr230 (loop C), and beta2Trp82 (loop D) and the nonconserved beta2Thr84; however, only alpha4Trp182 was predicted to contact bound antagonist, suggesting alpha4Tyr230, beta2Trp82, and beta2Thr84 contribute allosterically to the closed state elicited by bound antagonist. In addition, homology modeling predicted strong ionic interactions between the ammonium center of the Erythrina alkaloids and beta2Asp196, leading to the uncapping of loop C. Consistent with this, beta2D196A abolished sensitivity to inhibition by DHbetaE or erysodine but not by epierythratidine, which is not predicted to form ionic bonds with beta2Asp196. This residue is not conserved in subunits that comprise nAChRs with low sensitivity to inhibition by DHbetaE or erysodine, which highlights beta2Asp196 as a major determinant of the receptor selectivity of Erythrina alkaloids. PMID:20547737

  17. Molecular Determinants for Competitive Inhibition of ?4?2 Nicotinic Acetylcholine Receptors

    PubMed Central

    Carbone, Annalisa; García-Beltrán, Olimpo; Livingstone, Phil D.; Biggin, Philip C.; Cassels, Bruce K.; Wonnacott, Susan; Zapata-Torres, Gerald; Bermudez, Isabel

    2010-01-01

    The Erythrina alkaloids erysodine and dihydro-?-erythroidine (DH?E) are potent and selective competitive inhibitors of ?4?2 nicotinic acetylcholine receptors (nAChRs), but little is known about the molecular determinants of the sensitivity of this receptor subtype to inhibition by this class of antagonists. We addressed this issue by examining the effects of DH?E and a range of aromatic Erythrina alkaloids on [3H]cytisine binding and receptor function in conjunction with homology models of the ?4?2 nAChR, mutagenesis, and functional assays. The lactone group of DH?E and a hydroxyl group at position C-16 in aromatic Erythrina alkaloids were identified as major determinants of potency, which was decreased when the conserved residue Tyr126 in loop A of the ?4 subunit was substituted by alanine. Sensitivity to inhibition was also decreased by substituting the conserved aromatic residues ?4Trp182 (loop B), ?4Tyr230 (loop C), and ?2Trp82 (loop D) and the nonconserved ?2Thr84; however, only ?4Trp182 was predicted to contact bound antagonist, suggesting ?4Tyr230, ?2Trp82, and ?2Thr84 contribute allosterically to the closed state elicited by bound antagonist. In addition, homology modeling predicted strong ionic interactions between the ammonium center of the Erythrina alkaloids and ?2Asp196, leading to the uncapping of loop C. Consistent with this, ?2D196A abolished sensitivity to inhibition by DH?E or erysodine but not by epierythratidine, which is not predicted to form ionic bonds with ?2Asp196. This residue is not conserved in subunits that comprise nAChRs with low sensitivity to inhibition by DH?E or erysodine, which highlights ?2Asp196 as a major determinant of the receptor selectivity of Erythrina alkaloids. PMID:20547737

  18. REGULAR ARTICLE Glucocorticoid receptor antagonist and siRNA prevent

    E-print Network

    Salem, Aliasger K.

    marrow mesenchymal stromal cells in vitro Na Wei & Yang Yu & Vijaya Joshi & Thomas Schmidt & Fang Qian mesenchymal stromal/stem cells (MSCs) and on their senescence and antioxidant levels during extended in vitro or estrogen depletion. Keywords Glucocorticoid receptor . siRNA . RU486 . Mesenchymal stromal cells

  19. Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist.

    PubMed

    Bandaru, Srinivas; Marri, Vijaya Kumar; Kasera, Priyadarshani; Kovuri, Purnima; Girdhar, Amandeep; Mittal, Deepti Raj; Ikram, Sabeen; Gv, Ravi; Nayarisseri, Anuraj

    2014-01-01

    Montelukast and Zafirlukast are known leukotriene receptor antagonists prescribed in asthma treatment. However, these fall short as mono therapy and are frequently used in combination with inhaled glucocorticosteroids with or without long acting beta 2 agonists. Therefore, it is of interest to apply ligand and structure based virtual screening strategies to identify compounds akin to lead compounds Montelukast and Zafirlukast. Hence, compounds with structures having 95% similarity to these compounds were retrieved from NCBI?s PubChem database. Compounds similar to lead were grouped and docked at the antagonist binding site of cysteinyl leukotriene receptor 1. This exercise identified compounds UNII 70RV86E50Q (Pub Cid 71587778) and Sure CN 9587085 (Pub Cid 19793614) with higher predicted binding compared to Montelukast and Zafirlukast. It is shown that the compound Sure CN 9587085 showed appreciable ligand receptor interaction compared to UNII 70RV86E50Q. Thus, the compound Sure CN 9587085 is selected as a potent antagonist to cysteinyl leukotriene receptor 1 for further consideration in vitro and in vivo validation. PMID:25489175

  20. Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist

    PubMed Central

    Bandaru, Srinivas; Marri, Vijaya Kumar; Kasera, Priyadarshani; Kovuri, Purnima; Girdhar, Amandeep; Mittal, Deepti Raj; Ikram, Sabeen; GV, Ravi; Nayarisseri, Anuraj

    2014-01-01

    Montelukast and Zafirlukast are known leukotriene receptor antagonists prescribed in asthma treatment. However, these fall short as mono therapy and are frequently used in combination with inhaled glucocorticosteroids with or without long acting beta 2 agonists. Therefore, it is of interest to apply ligand and structure based virtual screening strategies to identify compounds akin to lead compounds Montelukast and Zafirlukast. Hence, compounds with structures having 95% similarity to these compounds were retrieved from NCBI?s PubChem database. Compounds similar to lead were grouped and docked at the antagonist binding site of cysteinyl leukotriene receptor 1. This exercise identified compounds UNII 70RV86E50Q (Pub Cid 71587778) and Sure CN 9587085 (Pub Cid 19793614) with higher predicted binding compared to Montelukast and Zafirlukast. It is shown that the compound Sure CN 9587085 showed appreciable ligand receptor interaction compared to UNII 70RV86E50Q. Thus, the compound Sure CN 9587085 is selected as a potent antagonist to cysteinyl leukotriene receptor 1 for further consideration in vitro and in vivo validation. PMID:25489175

  1. Interactions of tachykinin receptor antagonists with lipopolysaccharide-induced airway inflammation in mice.

    PubMed

    Veron, M; Guenon, I; Nenan, S; Emonds-Alt, X; Advenier, C; Lagente, V; Boichot, E

    2004-09-01

    1. Several observations suggest that tachykinins are involved in the pathogenesis of bronchopulmonary alterations. We have investigated the effect of antagonists for tachykinin NK1 (SR 140333), NK2 (SR 48968) or NK3 (SR 142801) receptors on inflammatory cell recruitment, tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 release and matrix metalloproteinase (MMP)-9 activity in the bronchoalveolar lavage fluid (BALF) of mice exposed to lipopolysaccharide (LPS; 100 microg/mL aerosol for 30 min). 2. Treatment of mice with a combination of SR 140333 and SR 48968 (10(-6) mol/L, aerosol) significantly reduced the increase in the number of total cells and neutrophils and MMP-9 activity in the BALF of mice 2.5 h after LPS exposure. Treatment with the NK3 antagonist SR 142801 (10(-6) mol/L, aerosol) did not inhibit the influx of neutrophils, but markedly reduced the increase in TNF-alpha and IL-6 levels at 2.5 h and MMP-9 activity at 20 h. 3. These results show that the three tachykinin receptor antagonists may interfere with the development of airway inflammation, namely neutrophilia, TNF-alpha release or MMP-9 activity in the BALF of mice exposed to LPS and suggest that not only NK1 and NK2 receptors, but also NK3 receptors are involved in the modulation of the inflammatory response and airway remodelling. PMID:15479172

  2. Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs.

    PubMed

    Moreaux, B; Nemmar, A; Vincke, G; Halloy, D; Beerens, D; Advenier, C; Gustin, P

    2000-11-24

    The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in the tracheo-bronchial tree and the effects of substance P and of tachykinin receptor antagonists on citric acid-induced cough. Citric acid exposure significantly increased substance P concentration in both broncho-alveolar and tracheal lavage fluids, while it decreased significantly the substance P content in tracheal mucosa. Substance P did not elicit cough, but significantly potentiated the citric acid-induced cough frequency. Tachykinin NK(1), NK(2) or NK(3) receptor antagonists, SR 140333 (nolpitantium), SR 48968 (saredutant) and SR 142801 (osanetant), respectively, significantly inhibited citric acid-induced cough. The same inhibitory effect of tachykinin receptor antagonists was observed, when substance P was nebulised before citric acid challenge. We conclude that citric acid induces in pigs a release of substance P in the tracheo-bronchial tree, which plays a sensitising role on the cough reflex. The involvement of tachykinin NK(1), NK(2), NK(3) receptors are also demonstrated in this reflex. PMID:11090648

  3. Antagonists of GLU(K5)-containing kainate receptors prevent pilocarpine-induced limbic seizures.

    PubMed

    Smolders, Ilse; Bortolotto, Zuner A; Clarke, Vernon R J; Warre, Ruth; Khan, Ghous M; O'Neill, Michael J; Ornstein, Paul L; Bleakman, David; Ogden, AnnMarie; Weiss, Brianne; Stables, James P; Ho, Ken H; Ebinger, Guy; Collingridge, Graham L; Lodge, David; Michotte, Yvette

    2002-08-01

    Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy. PMID:12080343

  4. Adenosine A2A Receptor Antagonists and Parkinson’s Disease

    PubMed Central

    2011-01-01

    This Review summarizes and updates the work on adenosine A2A receptor antagonists for Parkinson’s disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinson’s disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on preparing selective A2A antagonists, but a few approaches to dual A2A/A1 antagonists will also be highlighted. The in vivo profiles of compounds will be highlighted and discussed to compare activities across different chemical series. A clinical report and update will be given on compounds that have entered clinical trials. PMID:22860156

  5. Design and Synthesis of 4-(4-Benzoylaminophenoxy)phenol Derivatives As Androgen Receptor Antagonists

    PubMed Central

    2013-01-01

    We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 ?M), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 ?M), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 ?M). Structure–activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents. PMID:24900588

  6. Discovery of novel purine-based heterocyclic P2X7 receptor antagonists.

    PubMed

    Kwak, Seung-Hwa; Lee, Won-Gil; Lee, Yun-Jin; Lee, So-Deok; Kim, Yong-Chul; Ko, Hyojin

    2015-08-01

    The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X7 receptor antagonist 5 (IC50=13nM in hP2X7-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC50 value of 176±37nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1? release in THP-1 cells stimulated with LPS/IFN-?/BzATP (IC50=120±15nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse). PMID:26123174

  7. High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.

    PubMed Central

    Yanofsky, S D; Baldwin, D N; Butler, J H; Holden, F R; Jacobs, J W; Balasubramanian, P; Chinn, J P; Cwirla, S E; Peters-Bhatt, E; Whitehorn, E A; Tate, E H; Akeson, A; Bowlin, T L; Dower, W J; Barrett, R W

    1996-01-01

    Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist. PMID:8693002

  8. High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.

    PubMed

    Yanofsky, S D; Baldwin, D N; Butler, J H; Holden, F R; Jacobs, J W; Balasubramanian, P; Chinn, J P; Cwirla, S E; Peters-Bhatt, E; Whitehorn, E A; Tate, E H; Akeson, A; Bowlin, T L; Dower, W J; Barrett, R W

    1996-07-01

    Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist. PMID:8693002

  9. Persistent anxiolytic affects after chronic administration of the CRF1 receptor antagonist R121919 in rats

    PubMed Central

    Gutman, David A.; Owens, Michael J.; Thrivikraman, K.V.; Nemeroff, Charles B.

    2011-01-01

    Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF1 receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF1 receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained. This study evaluated the effects of long term (~4 week) treatment with the CRF1 receptor antagonist R121919, on CRF receptor function, HPA axis activity, behavioral measures, adrenal gland size, and body weight gain. Animals treated with 20 mg/kg/day of R121919 spent significantly more time in the open field in a defensive withdrawal test (138±36 seconds for R121919 vs 52±12 seconds for vehicle, p=0.01). No significant effect of chronic CRF1 receptor blockade on basal ACTH or corticosterone concentrations were detected, nor were significant changes detected in an elevated plus maze test. Both vehicle- and R121919- treated rats showed increases in AUC and peak ACTH and corticosterone concentrations following air puff startle stress, without any overall group differences, although a clear but non-significant attenuation in HPA axis response was observable in R121919 treated animals. Chronic CRF1 receptor blockade increased CRF peptide mRNA expression in the PVN and decreased CRF peptide mRNA expression in the central nucleus of the amygdala. Overall our results suggest that anxiolytic effects of chronic CRF1 receptor antagonism persist following chronic administration without significant attenuation of the HPA axis’s ability to mount a stress response. PMID:20951149

  10. Evidence for allosteric interactions of antagonist binding to the smoothened receptor.

    PubMed

    Rominger, Cynthia M; Bee, Wei-Lin Tiger; Copeland, Robert A; Davenport, Elizabeth A; Gilmartin, Aidan; Gontarek, Richard; Hornberger, Keith R; Kallal, Lorena A; Lai, Zhihong; Lawrie, Kenneth; Lu, Quinn; McMillan, Lynette; Truong, Maggie; Tummino, Peter J; Turunen, Brandon; Will, Matthew; Zuercher, William J; Rominger, David H

    2009-06-01

    The Smoothened receptor (Smo) mediates hedgehog (Hh) signaling critical for development, cell growth, and migration, as well as stem cell maintenance. Aberrant Hh signaling pathway activation has been implicated in a variety of cancers, and small-molecule antagonists of Smo have entered human clinical trials for the treatment of cancer. Here, we report the biochemical characterization of allosteric interactions of agonists and antagonists for Smo. Binding of two radioligands, [(3)H]3-chloro-N-[trans-4-(methylamino)cyclohexyl]-N-{[3-(4-pyridinyl)-phenyl]methyl}-1-benzothiophene-2-carboxamide (SAG-1.3) (agonist) and [(3)H]cyclopamine (antagonist), was characterized using human Smo expressed in human embryonic kidney 293F membranes. We observed full displacement of [(3)H]cyclopamine by all Smo agonist and antagonist ligands examined. N-[(1E)-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)methylidene]-4-(phenylmethyl)-1-piperazinamine (SANT-1), an antagonist, did not fully inhibit the binding of [(3)H]SAG-1.3. In a functional cell-based beta-lactamase reporter gene assay, SANT-1 and N-[3-(1H-benzimidazol-2-yl)-4-chlorophenyl]-3,4,5-tris(ethyloxy)-benzamide (SANT-2) fully inhibited 3-chloro-4,7-difluoro-N-[trans-4-(methylamino)cyclohexyl]-N-{[3-(4-pyridinyl)phenyl]methyl}-1-benzothiophene-2-carboxamide (SAG-1.5)-induced Hh pathway activation. Detailed "Schild-type" radioligand binding analysis with [(3)H]SAG-1.3 revealed that two structurally distinct Smoothened receptor antagonists, SANT-1 and SANT-2, bound in a manner consistent with that of allosteric modulation. Our mechanism of action characterization of radioligand binding to Smo combined with functional data provides a better understanding of small-molecule interactions with Smo and their influence on the Hh pathway. PMID:19304771

  11. The action of prostanoid receptor agonists and antagonists on smooth muscle and platelets.

    PubMed Central

    Eglen, R. M.; Whiting, R. L.

    1988-01-01

    1. Prostanoid receptors have been characterized in a range of guinea-pig and rat smooth muscle and platelets, according to the scheme of Coleman et al., (1985a), using agonists (prostaglandin D2 (PGD2), PGE1, PGE2, 16,16 dimethyl PGE2, PGF2 alpha, PGI2 and U46619) and putative selective antagonists (AH 6809 and SQ 29,548). 2. The ileum possesses EP1- and IP-receptors; the trachea, EP1-EP2- and TP-receptors; the oesophageal muscularis mucosa, EP1- and TP-receptors; the aorta and the portal vein TP-receptors. The rat colon possesses IP-, FP- and TP-receptors. 3. Guinea-pig platelets possess both IP and DP receptors mediating an inhibition of aggregation and TP receptors mediating proaggregation responses. No evidence was found for the presence of EP1-, EP2- or FP-receptors. 4. Misoprostol and fenprostalene were characterized using the above preparations. Misoprostol acts as a selective EP1-agonist, and has little or no DP, FP, IP and TP activity. In the trachea precontracted with carbachol no evidence of EP2-receptor stimulation was observed. Fenprostalene possesses FP and TP activity but no EP1, EP2, DP or IP activity. PMID:3134971

  12. Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.

    PubMed

    Bonaventura, Jordi; Navarro, Gemma; Casadó-Anguera, Verònica; Azdad, Karima; Rea, William; Moreno, Estefanía; Brugarolas, Marc; Mallol, Josefa; Canela, Enric I; Lluís, Carme; Cortés, Antoni; Volkow, Nora D; Schiffmann, Serge N; Ferré, Sergi; Casadó, Vicent

    2015-07-01

    Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain. PMID:26100888

  13. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease.

    PubMed

    Upton, Neil; Chuang, Tsu Tshen; Hunter, Ann J; Virley, David J

    2008-07-01

    Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach. PMID:18625457

  14. Darifenacin: a novel M3 muscarinic selective receptor antagonist for the treatment of overactive bladder.

    PubMed

    Chapple, Christopher R

    2004-11-01

    Darifenacin is a novel M3 muscarinic selective receptor antagonist for once-daily treatment of overactive bladder (OAB), a highly prevalent, chronic and debilitating disease defined by urinary urgency with or without urge incontinence, usually with increased frequency of micturition and nocturia. In vitro, darifenacin is a potent and specific muscarinic receptor antagonist with receptors relative to other muscarinic receptor subtypes. This profile may, therefore, confer clinical efficacy in the treatment of OAB, with a lower propensity for adverse effects and safety issues related to blockade of other muscarinic receptor subtypes. Indeed, consistent with its low relative affinity for M1 and M2 receptors, no effects on cognitive function and heart-rate variability, respectively, have been observed with darifenacin. Subsequent large-scale clinical trials have confirmed that darifenacin (at doses of 7.5 and 15 mg/day) results in central nervous system and cardiac adverse events comparable to placebo, and provides early and meaningful improvement across a range of OAB symptoms including incontinence episodes, urgency and urinary frequency. On the basis of such findings, darifenacin would appear to meet the current need for an effective OAB pharmacotherapy that is efficacious, well-tolerated and, more importantly, minimises the risk of safety-related adverse effects. PMID:15500396

  15. Central opioid receptor subtype antagonists differentially reduce intake of saccharin and maltose dextrin solutions in rats.

    PubMed

    Beczkowska, I W; Koch, J E; Bostock, M E; Leibowitz, S F; Bodnar, R J

    1993-08-01

    Opioid modulation of ingestion includes general opioid antagonism of deprivation-induced water intake and intake of sucrose and saccharin solutions. Previous studies using selective subtype antagonists indicated that opioid effects upon deprivation-induced water intake occurred through the mu2 receptor and that opioid effects upon sucrose intake occurred through kappa and mu2 receptors. The present study compared the effects of intracerebroventricular administration of opioid receptor subtype antagonists upon intakes of a saccharin solution and a maltose dextrin (MD) solution to determine which receptor subtypes were involved in modulation of ingestion of different preferred tastants. Significant reductions in saccharin intake (1 h) occurred following naltrexone (20-50 micrograms: 66%) and naltrindole (delta, 20 micrograms: 75%), whereas [D-Ala2, Leu5, Cys6]-enkephalin (DALCE, delta 1, 40 micrograms: 45%) had transient (5 min) effects. Neither beta-funaltrexamine (B-FNA, mu), naloxonazine (mu1), nor nor-binaltorphamine (Nor-BNI, kappa) significantly altered saccharin intake. Significant reductions in MD intake (1 h) occurred following naltrexone (5-50 micrograms: 69%) and B-FNA (1-20 micrograms: 38%). MD intake was not reduced by naltrindole, DALCE, naloxonazine and Nor-BNI. Peak antagonist effects were delayed (20-25 min) to reflect interference with the maintenance, rather than the initiation of saccharin or MD intake. Comparisons of opioid antagonist effects across intake situations revealed that naltrexone had consistently low ID40 values for saccharin (29 nmol), MD (25 nmol), sucrose (6 nmol) and deprivation (38 nmol) intake. Despite its significant effects relative to naloxonazine, B-FNA had significantly higher ID40 values for saccharin (800 nmol), MD (763 nmol) and sucrose (508 nmol) relative to deprivation (99 nmol) intake, suggesting that mu2 receptors may be mediating maintenance of intake rather than taste effects. Nor-BNI had low ID40 values for intake of sucrose (4 nmol), but not for saccharin (168 nmol), MD (153 nmol) and deprivation (176 nmol), suggesting that kappa receptors may mediate ingestion of sweet-tasting stimuli. That delta (naltrindole: ID40 = 60 nmol), but not delta 1 (DALCE: ID40 = 288 nmol) antagonists consistently reduce saccharin intake suggests a role for the delta 2 receptor subtype in the modulation of hedonic orosensory signals. PMID:8397050

  16. Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors.

    PubMed

    Lodge, David; Tidball, Patrick; Mercier, Marion S; Lucas, Sarah J; Hanna, Lydia; Ceolin, Laura; Kritikos, Minos; Fitzjohn, Stephen M; Sherwood, John L; Bannister, Neil; Volianskis, Arturas; Jane, David E; Bortolotto, Zuner A; Collingridge, Graham L

    2013-11-01

    Metabotropic glutamate (mGlu) receptors are implicated in many neurological and psychiatric diseases and are the targets of therapeutic agents currently in clinical development. Their activation has diverse effects in the central nervous system (CNS) that includes an involvement in synaptic plasticity. We previously reported that the brief exposure of hippocampal slices to dihydroxyphenylglycine (DHPG) can result in a long-term depression (LTD) of excitatory synaptic transmission. Surprisingly, this LTD could be fully reversed by mGlu receptor antagonists in a manner that was itself fully reversible upon washout of the antagonist. Here, 15 years after the discovery of DHPG-LTD and its reversible reversibility, we summarise these initial findings. We then present new data on DHPG-LTD, which demonstrates that evoked epileptiform activity triggered by activation of group I mGlu receptors can also be reversibly reversed by mGlu receptor antagonists. Furthermore, we show that the phenomenon of reversible reversibility is not specific to group I mGlu receptors. We report that activation of group II mGlu receptors in the temporo-ammonic pathway (TAP) and mossy fibre pathway within the hippocampus and in the cortical input to neurons of the lateral amygdala induces an LTD that is reversed by LY341495, a group II mGlu receptor antagonist. We also show that activation of group III mGlu8 receptors induces an LTD at lateral perforant path inputs to the dentate gyrus and that this LTD is reversed by MDCPG, an mGlu8 receptor antagonist. In conclusion, we have shown that activation of representative members of each of the three groups of mGlu receptors can induce forms of LTD than can be reversed by antagonists, and that in each case washout of the antagonist is associated with the re-establishment of the LTD. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID:23542080

  17. Conformational states of the nicotinic acetylcholine receptor from Torpedo californica induced by the binding of agonists, antagonists, and local anesthetics. Equilibrium measurements using tritium-hydrogen exchange

    SciTech Connect

    McCarthy, M.P.; Stroud, R.M.

    1989-01-10

    The tritium-hydrogen exchange kinetics of Torpedo californica AChR, in native membrane vesicles at pH 7.4 and 0 degrees C, have been analyzed in the presence of agonists, partial agonists, local anesthetics, and competitive antagonists. The agonists carbamylcholine (10 microM-1 mM) and suberyldicholine (10 microM) and the partial agonists decamethonium (25 microM and 1 mM) and hexamethonium (1 mM) have no effect on the exchange kinetics, although at lower concentration carbamylcholine may slightly accelerate exchange. Nondesensitizing local anesthetics do affect the exchange behavior, dependent on concentration. Procaine at 500 microM moderately retards exchange while procaine at 10 mM and tetracaine at 5 mM slightly accelerate exchange. The competitive antagonist alpha-bungarotoxin retards exchange significantly, as does d-tubocurarine although to a lesser extent. These results suggest that the resting and desensitized conformations of the AChR are very similar in overall solvent accessibility and that at lower concentrations noncompetitive blockers such as procaine may stabilize a less solvent-accessible state of the AChR. The competitive antagonists alpha-bungarotoxin and d-tubocurare also stabilize a dynamically restricted, less solvent-accessible conformation of the acetylcholine receptor, demonstrating that a large conformational change accompanies binding of these toxins. Any change in conformation which may accompany desensitization is very different from these effects.

  18. Identification of surrogate agonists and antagonists for orphan G-protein-coupled receptor GPR139.

    PubMed

    Hu, Liaoyuan A; Tang, Pauline M; Eslahi, Nima K; Zhou, Tian; Barbosa, Joseph; Liu, Qingyun

    2009-08-01

    GPR139 is an orphan G-protein-coupled receptor (GPCR) that is expressed nearly exclusively in the central nervous system and may play a role in the control of locomotor activity. The signal transduction pathway and pharmacological function of GPR139, however, are still controversial due to the lack of natural or synthetic ligands. The authors report the characterization of human GPR139 signaling pathway and identification of surrogate agonists and antagonists. In both transient and stable transfections of HEK293F cells, overexpression of GPR139 increased basal intracellular cAMP concentrations compared to control cells. Furthermore, forskolin and isoproterenol-stimulated cAMP responses were enhanced in GPR139-expressing cells, suggesting that GPR139 is predominantly coupled to Galpha(s). The authors screened a large library of small molecules for compounds that increase cAMP levels in GPR139-expressing cells and identified a compound with GPR139 agonist activity. This compound increased cAMP production specifically in cells expressing GPR139 but not in cells expressing its highly homologous receptor GPR142. Furthermore, this compound did not induce calcium mobilization in GPR139 cells, indicating no Galpha(q)-mediated response. In addition, antagonist screening with the identified agonist yielded 2 classes of compounds as antagonists. The identification of surrogate agonists and antagonists of human GPR139 provides important tools for further study of this orphan GPCR. PMID:19525486

  19. Treatment and prevention of various therapeutic conditions using OX receptor antagonistic activity (WO2012081692).

    PubMed

    Christopher, John A; Congreve, Miles S

    2013-02-01

    Application WO2012081692 from Taisho Pharmaceutical Co. Ltd. claims pyrazole-based antagonists of the orexin-1 and orexin-2 receptors. Utility in a number of therapeutic areas is claimed, including the treatment of sleep disorders; the most likely use of the claimed compounds. Data from in vitro functional assays are presented, with the claimed compounds typically being dual orexin receptor antagonists (DORAs) or having moderate selectivity for orexin-1. Structurally, the claimed compounds represent a variation on established DORA SAR themes and translate features of clinical compounds into a pyrazole-based scaffold. Example 52, the most potent molecule in the application, has similar molecular weight and lipophilicity to suvorexant, the most advanced DORA, with broadly comparable potency in functional assays. PMID:23282091

  20. Antidepressant-like effects of CCK B receptor antagonists: involvement of the opioid system

    Microsoft Academic Search

    Fernando Hernando; José A. Fuentes; Marie-Claude Fournié-Zaluski; Bernard P. Roques; Mariano Ruiz-Gayo

    1996-01-01

    RB 101 (N-[(R,S)-2-benzyl-3-[(S)-2-amino-4-methylthiobutyldithio]-1-oxopropyl]-l-phenylalaninebenzyl ester), a systemically active inhibitor of enkephalin catabolism, has been shown to elicit antidepressant-like effects in mice, both in the forced-swimming and in the conditioned suppression of the mobility tests. The same type of response has been also observed following administration of the cholecystokinin CCKB receptor antagonist L-365,260 ((3R)-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-methylphenylurea). Interestingly, the ?-opioid receptor antagonist naltrindole (17-cyclopropylmethyl-6,7-dehydro-4,5?-epoxy-3,14-dihydroxy-6,7,2?-3?-indolomorphinan) blocks

  1. Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids

    PubMed Central

    2011-01-01

    Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (Ki < 10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C19 > 1 ?M). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development. PMID:24900284

  2. Peripherally acting mu-opioid receptor antagonists and postoperative ileus: mechanisms of action and clinical applicability.

    PubMed

    Viscusi, Eugene R; Gan, Tong J; Leslie, John B; Foss, Joseph F; Talon, Mark D; Du, Wei; Owens, Gay

    2009-06-01

    Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed. PMID:19448206

  3. Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

    PubMed

    Degnan, Andrew P; Tora, George O; Han, Ying; Rajamani, Ramkumar; Bertekap, Robert; Krause, Rudolph; Davis, Carl D; Hu, Joanna; Morgan, Daniel; Taylor, Sarah J; Krause, Kelly; Li, Yu-Wen; Mattson, Gail; Cunningham, Melissa A; Taber, Matthew T; Lodge, Nicholas J; Bronson, Joanne J; Gillman, Kevin W; Macor, John E

    2015-08-01

    Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection. PMID:26048800

  4. 2,3-Diaminopyridine as a platform for designing structurally unique nonpeptide bradykinin B 1 receptor antagonists

    Microsoft Academic Search

    Dong-Mei Feng; Jenny M. Wai; Scott D. Kuduk; Christina Ng; Kathy L. Murphy; Richard W. Ransom; Duane Reiss; Raymond S. L. Chang; Charles M. Harrell; Tanya MacNeil; Cuyue Tang; Thomayant Prueksaritanont; Roger M. Freidinger; Douglas J. Pettibone; Mark G. Bock

    2005-01-01

    A novel class of 2,3-diaminopyridine bradykinin B1 receptor antagonists is disclosed. Structure–activity relationship studies (SARs) that led to compounds with significantly improved potency and pharmacokinetic properties relative to the lead compound are described.

  5. The pharmacological rationale for combining muscarinic receptor antagonists and ?-adrenoceptor agonists in the treatment of airway and bladder disease?

    PubMed Central

    Dale, Philippa R; Cernecka, Hana; Schmidt, Martina; Dowling, Mark R; Charlton, Steven J; Pieper, Michael P; Michel, Martin C

    2014-01-01

    Muscarinic receptor antagonists and ?-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and ?-adrenoceptors are physiological antagonists for smooth muscle tone in airways and bladder. Muscarinic agonism may attenuate ?-adrenoceptor-mediated relaxation more than other contractile stimuli. Chronic treatment with one drug class may regulate expression of the target receptor but also that of the opposing receptor. Prejunctional ?2-adrenoceptors can enhance neuronal acetylcholine release. Moreover, at least in the airways, muscarinic receptors and ?-adrenoceptors are expressed in different locations, indicating that only a combined modulation of both systems may cause dilatation along the entire bronchial tree. While all of these factors contribute to a rationale for a combination of muscarinic receptor antagonists and ?-adrenoceptor agonists, the full value of such combination as compared to monotherapy can only be determined in clinical studies. PMID:24682092

  6. Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods.

    PubMed

    Bhattacharjee, Apurba K; Pomponio, James W; Evans, Sarah A; Pervitsky, Dmitry; Gordon, Richard K

    2013-05-01

    Muscarinic acetylcholine receptors (mAChRs) have five known subtypes which are widely distributed in both the peripheral and central nervous system for regulation of a variety of cholinergic functions. Atropine is a well known muscarinic subtype non-specific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites. Atropine is used to treat organophosphate (OP) poisoning and resulting seizures in the warfighter because it competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors. ACh accumulates due to OP inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh. However, atropine produces several unwanted side-effects including dilated pupils, blurred vision, light sensitivity, and dry mouth. To overcome these side-effects, our goal was to find an alternative to atropine that emphasizes M1 (seizure prevention) antagonism but has minimum M2 (cardiac) and M3 (e.g., eye) antagonism so that an effective less toxic medical countermeasure may be developed to protect the warfighter against OP and other chemical warfare agents (CWAs). We adopted an in silico pharmacophore modeling strategy to develop features that are characteristics of known M1 subtype-selective compounds and used the model to identify several antagonists by screening an in-house (WRAIR-CIS) compound database. The generated model for the M1 selectivity was found to contain two hydrogen bond acceptors, one aliphatic hydrophobic, and one ring aromatic feature distributed in a 3D space. From an initial identification of about five hundred compounds, 173 compounds were selected through principal component and cluster analyses and in silico ADME/Toxicity evaluations. Next, these selected compounds were evaluated in a subtype-selective in vitro radioligand binding assay. Twenty eight of the compounds showed antimuscarinic activity. Nine compounds showed specificity for M1 receptors and low specificity for M3 receptors. The pK(i) values of the compounds range from 4.5 to 8.5 nM in comparison to a value of 8.7 nM for atropine. 2-(diethylamino)ethyl 2,2-diphenylpropanoate (ZW62841) was found have the best desired selectivity. None of the newly found compounds were previously reported to exhibit antimuscarinic specificity. Both theoretical and experimental results are presented. PMID:23523385

  7. Antagonistic properties of McNeil-A-343 at 5-HT4 and 5-HT3 receptors.

    PubMed Central

    Sagrada, A; Schiavi, G B; Cereda, E; Ladinsky, H

    1994-01-01

    1. This study describes the in vitro interaction of the muscarinic ligand McNeil-A-343 with two 5-hydroxytryptamine (5-HT) receptor subtypes, the 5-HT4 and 5-HT3 receptors, using functional as well as radioligand binding studies. 2. In the rat oesophageal muscularis mucosae, precontracted with carbachol, McNeil-A-343 was a competitive antagonist (pA2 6.2) of the 5-HT4 receptor which mediates the relaxation induced by 5-HT. The compound per se relaxed the oesophagus at high concentration only (> or = 10 microM), an effect unchanged by desensitization of the 5-HT4 receptor with 10 microM 5-methoxytryptamine. In the same preparation in the absence of tone, McNeil-A-343 displaced the carbachol concentration-response curve to the right, yielding an apparent affinity (pA2) of 4.9 for muscarinic receptors. 3. In the rat isolated superior cervical ganglion preparation, after blockade of muscarinic and nicotinic receptors, McNeil-A-343 caused a concentration-dependent depolarization that was unaffected by 100 nM ondansetron. The concentration-fast depolarization curve to 5-HT, mediated by the 5-HT3 receptor, was displaced to the right by McNeil-A-343, which showed an apparent affinity (pA2) of 4.8 for the 5-HT3 subtype. 4. In binding studies, McNeil-A-343 recognized a single population of 5-HT4 receptors in pig caudate nucleus, with a pKI of 5.9. The binding affinity of McNeil-A-343 for 5-HT3 receptors in NG 108-15 cells was approximately four times lower (pKI 5.3). Binding affinities (pKI) for muscarinic receptor subtypes in rat tissues were 5.3 (M1, cortex), 5.2 (M2, heart) and 4.9 (M3, submandibular glands), respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7532081

  8. The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

    SciTech Connect

    Ribeiro, Mariana P.C. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Nunes-Correia, Isabel [Center for Neuroscience and Cell Biology, Flow Cytometry Unit, University of Coimbra, 3000-354 Coimbra (Portugal); Santos, Armanda E., E-mail: aesantos@ci.uc.pt [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Custódio, José B.A. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal)

    2014-02-15

    Recent reports suggest that N-methyl-D-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination. - Highlights: • MK-801 and memantine decrease melanoma cell proliferation. • The combination of MK-801 with antiestrogens inhibits melanoma cell proliferation. • These combinations greatly enhance the effects of the compounds individually. • MK-801 combined with tamoxifen active metabolites induces cell cycle arrest in G1. • The combination of MK-801 and antiestrogens is an innovative strategy for melanoma.

  9. An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

    PubMed Central

    Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgård, Ulf; Cowen, Edward W.; Pham, Tuyet-Hang; Booty, Matthew; Estes, Jacob D.; Sandler, Netanya G.; Plass, Nicole; Stone, Deborah L.; Turner, Maria L.; Hill, Suvimol; Butman, John A.; Schneider, Rayfel; Babyn, Paul; El-Shanti, Hatem I.; Pope, Elena; Barron, Karyl; Bing, Xinyu; Laurence, Arian; Lee, Chyi-Chia R.; Chapelle, Dawn; Clarke, Gillian I.; Ohson, Kamal; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin D.; Gregersen, Peter K.; van Hagen, P. Martin; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach-Mansky, Raphaela

    2010-01-01

    Background Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone. Methods We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN. Results We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1? stimulation. Patients treated with anakinra responded rapidly. Conclusions We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) PMID:19494218

  10. Effects of oxytocin receptor antagonist atosiban on pregnant myometrium in vitro

    Microsoft Academic Search

    Ulrich Büscher; Frank C.-K Chen; Eugénie Riesenkampff; Donata von Dehn; Matthias David; Joachim W Dudenhausen

    2001-01-01

    Objective:To investigate dose-dependent effects of oxytocin receptor antagonist, atosiban, on oxytocin-induced contractions of myometrial strips from healthy pregnant women.Methods:During elective cesareans, myometrial biopsies were taken from the lower uterine segment and trimmed into 2 × 2 × 10-mm longitudinal strips within 36 hours. One hundred twenty-two myometrial strips showed regular spontaneous contractions and were used for measurement. Each myometrial strip

  11. Influence of a GABA B receptor antagonist on the sleep–waking cycle in the rat

    Microsoft Academic Search

    Pierre Gauthier; Christian Arnaud; Gabriel Gandolfo; Claude Gottesmann

    1997-01-01

    The influence of CGP 35348 (a GABAB receptor antagonist) on the sleep–waking cycle was studied in rats. The animals were injected i.p. at the beginning of the light period and the data expressed by 2-h periods and total duration (6 h). At 100 mg\\/kg, slow-wave sleep (SWS) was decreased during the 6-h recording with a peculiar decrease during the first

  12. Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918.

    PubMed

    Paone, Daniel V; Nguyen, Diem N; Shaw, Anthony W; Burgey, Christopher S; Potteiger, Craig M; Deng, James Z; Mosser, Scott D; Salvatore, Christopher A; Yu, Sean; Roller, Shane; Kane, Stefanie A; Selnick, Harold G; Vacca, Joseph P; Williams, Theresa M

    2011-05-01

    In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918). PMID:21251825

  13. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks

    Microsoft Academic Search

    Gilbert Y. Wong; Narender R. Gavva

    2009-01-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence,

  14. Lansoprazole compared with histamine 2-receptor antagonists in healing gastric ulcers: a meta-analysis

    Microsoft Academic Search

    Sean R. Tunis; Iris A. Sheinhait; Christopher H. Schmid; Daren J. Bishop; Susan D. Ross

    1997-01-01

    To compare the gastric ulcer healing rates of lansoprazole with histamine2-receptor antagonists (H2RAs) (ranitidine, famotidine, cimetidine, and roxatidine), a meta-analysis was performed using data from five published and eight unpublished randomized controlled trials. Analyses were performed using (1) both evaluable patients (n = 1527) and all randomized patients (n = 1655) (assuming that patients lost to follow-up were treatment failures);

  15. Discovery and characterization of a potent and selective EP4 receptor antagonist.

    PubMed

    Schiffler, Matthew A; Chandrasekhar, Srinivasan; Fisher, Matthew J; Harvey, Anita; Kuklish, Steven L; Wang, Xu-Shan; Warshawsky, Alan M; York, Jeremy S; Yu, Xiao-Peng

    2015-08-15

    EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNF? production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included. PMID:26091726

  16. Low levels of interleukin-1 receptor antagonist coincide with kidney involvement in systemic lupus erythematosus

    Microsoft Academic Search

    G. STURFELT; P. ROUX-LOMBARD; F. A. WOLLHEIM; J.-M. DAYER

    1997-01-01

    SUMMARY The objective was to study the relationship between the levels of interleukin-1 receptor antagonist (IL-1Ra) and disease activ- ity and the acute-phase response in SLE patients with and without renal involvement. Twenty SLE patients who had distinct active clinical manifestations (eight glomerulonephritis, four systemic vasculitis without kidney involvement, nine skin rash, 12 arthritis, five serositis, four neuropsychiatric manifestations, three

  17. In vitro availability studies of enoxacin in presence of H2 receptor antagonists.

    PubMed

    Arayne, M Saeed; Sultana, Najma; Haroon, Urooj; Hamza, Erum

    2007-07-01

    Enoxacin is a second-generation quinolone with increased antibacterial activity both in potency as well as in terms of broad spectrum against a wide range of clinically important pathogens over the first generation quinolones and produces its effect by inhibiting bacterial enzyme DNA gyrase. There are a number of drug interactions reported for enoxacin. On the other hand H2-receptor antagonists block gastric acid secretion and some cardiovascular effects of histamine. As the later drugs are used for a long-term therapy, they may be coadministered with other drugs. In present study in vitro release of enoxacin in presence of cimetidine, ranitidine and famotidine has been studied on a B.P. 2003 dissolution test apparatus and compared with the availability of enoxacin and H2-receptor antagonists alone. The interacting drugs were analyzed spectrophotometrically. These studies were carried out in simulated gastric juice, simulating empty stomach, simulated intestinal juice (pH 9) and buffers of pH 7.4 simulating blood pH at 37 degrees C. In order to support these interaction studies, the effect of H2-receptor antagonists on the antibacterial efficacy (MIC) of enoxacin was also studied by turbidity method and compared with parent drug against Staphylococcus aureus, Streptococcus pyogens, Streptococcus pneumoniae, Enterococcus, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Bacillus subtilis. On the basis of these results, it is suggested that enoxacin should be coadministered with care along with H2-receptor antagonists especially in case of ranitidine, although chances of adverse reactions are rare but decrease in MIC of enoxacin may result in delayed effect or require prolonged use of the drug. PMID:17545110

  18. Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB1 receptor antagonist

    PubMed Central

    Wiley, Jenny L.; Breivogel, Christopher S.; Mahadevan, Anu; Pertwee, Roger G.; Cascio, Maria Grazia; Bolognini, Daniele; Huffman, John W.; Walentiny, D. Matthew; Vann, Robert E.; Razdan, Raj K.; Martin, Billy R.

    2010-01-01

    Rimonabant, the prototypic antagonist of cannabinoid CB1 receptors, has been reported to have inverse agonist properties at higher concentrations, which may complicate its use as a tool for mechanistic evaluation of cannabinoid pharmacology. Consequently, recent synthesis efforts have concentrated on discovery of a neutral antagonist using a variety of structural templates. The purpose of this study was to evaluate the pharmacological properties of the putative neutral cannabinoid CB1 receptor antagonist O-2050, a sulfonamide side chain analog of ?8-tetrahydrocannabinol. O-2050 and related sulfonamide cannabinoids exhibited good affinity for both cannabinoid CB1 and CB2 receptors. While the other sulfonamide analogs produced cannabinoid agonist effects in vivo (e.g., activity suppression, antinociception, and hypothermia), O-2050 stimulated activity and was inactive in the other two tests. O-2050 also decreased food intake in mice, an effect that was reminiscent of that produced by rimonabant. Unlike rimonabant, however, O-2050 did not block the effects of cannabinoid agonists in vivo, even when administered i.c.v. In contrast, O-2050 antagonized the in vitro effects of cannabinoid agonists in [35S]GTP?S and mouse vas deferens assays without having activity on its own in either assay. Further evaluation revealed that O-2050 fully and dose-dependently substituted for ?9-tetrahydrocannabinol in a mouse drug discrimination procedure (a cannabinoid agonist effect) and that it inhibited forskolin-stimulated cyclic AMP signaling with a maximum efficacy of approximately half that of the full agonist CP55,940 [(?)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol]. Together, these results suggest that O-2050 is not a viable candidate for classification as a neutral cannabinoid CB1 receptor antagonist. PMID:21114999

  19. IL1 Receptor Antagonist (IL1RA) Gene Polymorphism in Sjogren's Syndrome and Rheumatoid Arthritis

    Microsoft Academic Search

    S. Perrier; C. Coussediere; J. J. Dubost; E. Albuisson; B. Sauvezie

    1998-01-01

    The gene encoding interleukin-1 receptor antagonist (IL-1ra) has a variable allelic polymorphism. The IL1RN*2 allele was recently described as a factor of severity in several autoimmune diseases and was paradoxically associated with increased production of IL-1ra by monocytesin vitro.We studied this polymorphism in 36 patients with possible or definite primary Sjogren's syndrome and found that IL1RN*2 was significantly more frequent

  20. The cannabinoid 1 receptor antagonist AM251 produces nocifensive behavior via activation of ERK signaling pathway

    Microsoft Academic Search

    Soh Katsuyama; Hirokazu Mizoguchi; Takaaki Komatsu; Kohshi Nagaoka; Shinobu Sakurada; Tsukasa Sakurada

    2010-01-01

    Intrathecal (i.t.) injection of AM251, a cannabinoid 1 (CB1) receptor antagonist, into the spinal lumbar space of mice elicited a behavioral response consisting of biting and licking with a few scratchings. In this study, we investigated to determine whether i.t. AM251 could influence the activity of extracellular signal-regulated kinase-1 and -2 (ERK1\\/2), a mitogen-activated protein kinase (MAPK) in neuronal nitric

  1. Radiolabelled interleukin-1 receptor antagonist for detection of synovitis in patients with rheumatoid arthritis

    Microsoft Academic Search

    P. Barrera; C. J. van der Laken; O. C. Boerman; W. J. G. Oyen; M. T. P. van de Ven; F. H. M. Corstens

    2000-01-01

    Objectives. To investigate the distribution of radiolabelled interleukin-1 receptor antagonist (IL-1ra) in patients with rheumatoid arthritis (RA) and to assess whether this cytokine is suitable for scintigraphic visualization of synovitis. Methods. In patients with active RA, scintigraphy was performed after a single i.v. dose of (123I )IL-1ra. Clearance and organ distribution of radiolabelled IL-1ra were studied. To assess whether radiolabelled

  2. A high-performance liquid chromatographic method for screening angiotensin II receptor antagonists in human urine

    Microsoft Academic Search

    L. González; R. M. Alonso; R. M. Jiménez

    2000-01-01

    Summary  A high-performance liquid chromatographic method with photometric detection has been developed for the determination of five\\u000a angiotensin II receptor antagonists (ARA II): Losartan, Irbesartan, Valsartan, and Candesartan cilexetil and its metabolite\\u000a Candesartan M1. Reversedphase chromatography was performed at room temperature on a ?Bondapak C18 column; compounds were separated by gradient elution with mixtures of acetonitrile and 0.1 M acetate buffer,

  3. Estimation of the dissociation rate of unlabelled ligand–receptor complexes by a ‘two-step’ competition binding approach

    PubMed Central

    Packeu, A; Wennerberg, M; Balendran, A; Vauquelin, G

    2010-01-01

    BACKGROUND AND PURPOSE Because the in vivo effectiveness of ligands may also be determined by the rate by which they dissociate from their target receptors, drug candidates are being increasingly screened for this kinetic property. The dissociation rate of unlabelled ligand–receptor complexes can be estimated indirectly from their ability to slow the association of subsequently added radioligand molecules. EXPERIMENTAL APPROACH We used the ‘two-step competition’ binding approach consisting of pre-incubating the receptor preparation with a wide range of ligand concentrations, washing off free ligand molecules, adding radioligand and monitoring its receptor binding after a fixed time. Based on the rationale that binding of both ligands is mutually exclusive and that they bind according to the law of mass action to a single class of sites, the unlabelled ligand's disociation rate can be estimated from the upward shift that the competition curve experiences after washing. KEY RESULTS The relevance of the ‘two-step competition’ approach was explored by computer simulations and by comparing the dissociation behaviour of unlabelled D2 dopamine and CB1 cannabinoid receptor antagonists in this and alternative approaches. Besides providing satisfactory estimations of dissociation rates, the method also detects the ability of the unlabelled ligand molecules to be released from ‘sinks’ such as the cell membrane. CONCLUSIONS AND IMPLICATIONS As the ‘two-step competition’ requires rapid intermediate washing steps and needs radioligand binding to be measured at only one time point, this approach is particularly suited for binding studies on intact plated cells. PMID:20946109

  4. Differential Effects of Dopamine and AMPA Receptor Antagonists on the Expression of Conditioned Avoidance Responding in Rats

    Microsoft Academic Search

    Gregory A. Boivin; Richard J. Beninger

    2008-01-01

    AMPA receptor antagonists disrupt avoidance responding, but their day-to-day effect on this behavior has not been elucidated. This study compared the multisession effect of the AMPA\\/kainate receptor antagonist CNQX with that of the typical antipsychotic haloperidol on the expression of avoidance responding. Rats (N = 199) were trained to move to safety on presentation of a tone in one-way active

  5. 2Methyl6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist

    Microsoft Academic Search

    Fabrizio Gasparini; Kurt Lingenhöhl; Natacha Stoehr; Peter J Flor; Micheline Heinrich; Ivo Vranesic; Michel Biollaz; Hans Allgeier; Roland Heckendorn; Stephan Urwyler; Mark A Varney; Edwin C Johnson; Stephen D Hess; Sara P Rao; Aida I Sacaan; Emily M Santori; Gönul Veliçelebi; Rainer Kuhn

    1999-01-01

    In the present paper we describe 2-methyl-6-(phenylethynyl)-pyridine (MPEP) as a potent, selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGlu5). At the human mGlu5a receptor expressed in recombinant cells, MPEP completely inhibited quisqualate-stimulated phosphoinositide (PI) hydrolysis with an IC50 value of 36 nM while having no agonist or antagonist activities at cells expressing the human mGlu1b

  6. PSA-NCAM expression in the piriform cortex of the adult rat. Modulation by NMDA receptor antagonist administration

    Microsoft Academic Search

    Juan Nacher; Gregori Alonso-Llosa; Daniel Rosell; Bruce McEwen

    2002-01-01

    Administration of NMDA receptor antagonists upregulates the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the adult hippocampus. Since the piriform cortex is also populated by PSA-NCAM immunoreactive neurons during adulthood, we sought to characterize them in detail and to test whether NMDA receptor antagonists also modulate PSA-NCAM in this cortical region. PSA-NCAM immunoreactivity is

  7. Antagonist affinity measurements at the Gi-coupled human histamine H3 receptor expressed in CHO cells

    Microsoft Academic Search

    Jillian G Baker

    2008-01-01

    BACKGROUND: The H3 histamine receptor is a Gi-coupled GPCR that has been proven to exist in different agonist-induced states, including that defined by the protean agonist proxyfan. Several GPCRs are now known to exist in different states. For some of these, antagonist affinity measurement remain constant regardless of the state of the receptor, for others e.g. the beta-adrenoceptors, the antagonist

  8. Interleukin 1 Receptor Antagonist Deficiency Presenting as Infantile Pustulosis Mimicking Infantile Pustular Psoriasis

    PubMed Central

    Minkis, Kira; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Magro, Cynthia; Scott, Rachelle; Davis, Jessica G.; Sardana, Niti; Herzog, Ronit

    2012-01-01

    Background Deficiency of interleukin 1 receptor antagonist (DIRA) is a recently described autoinflammatory syndrome of skin and bone caused by recessive mutations in the gene encoding the interleukin 1 receptor antagonist. Few studies have been published about this debilitating condition. Early identification is critical for targeted lifesaving intervention. Observations A male infant, born to nonconsanguineous Puerto Rican parents, was referred for management of a pustular eruption diagnosed as pustular psoriasis. At 2 months of age, the infant developed a pustular eruption. After extensive evaluation, he was confirmed to be homozygous for a 175-kb genomic deletion on chromosome 2 that includes the IL1RN gene, commonly found in Puerto Ricans. Therapy with anakinra was initiated, with rapid clearance of skin lesions and resolution of systemic inflammation. Conclusions Recent identification of DIRA as a disease entity, compounded by the limited number of reported cases, makes early identification difficult. It is critical to consider this entity in the differential diagnosis of infantile pustulosis. Targeted therapy with the recombinant human interleukin 1 receptor antagonist anakinra can be lifesaving if initiated early. A high carrier frequency of the 175-kb DIRA-associated genomic deletion in the Puerto Rican population strongly supports testing infants presenting with unexplained pustulosis in patients from this geographic region. PMID:22431714

  9. Isolation and characterization of platelet-activating factor receptor binding antagonists from Biota orientalis.

    PubMed

    Yang, H O; Suh, D Y; Han, B H

    1995-02-01

    The leaf extract of Biota orientalis showed potent PAF receptor binding antagonistic activity in our previous screening studies on 234 Korean medicinal plants using rabbit platelet receptor binding tests. The activity-guided purification of the plant extract resulted in the isolation of six compounds, including two active substances. The chemical structures of the compounds isolated were established by chemical and spectrometric analyses as dotriacontane, totarol, 8 beta-hydroxy-3-oxopimar-15-ene, cedrol (IC50 = 1.3 x 10(-5) M), pinusolide (IC50 = 2.52 x 10(-7) M), and 5-hydroxy-7,4'-dimethoxyflavone. PMID:7700989

  10. Synergistic analgesic effects of intrathecal midazolam and NMDA or AMPA receptor antagonists in rats

    Microsoft Academic Search

    Tomoki Nishiyama; Laszlo Gyermek; Chingmuh Lee; Sachiko Kawasaki-Yatsugi; Tokio Yamaguchi

    2001-01-01

    Purpose: To investigate the interaction of midazolam and N-methyl-D-aspartate (NMDA) receptor or -amino-3-hydroxy-5-methyl isoxazole-4-propionic\\u000a acid (AMPA) receptor antagonist on the effects of persistent inflammatory nociceptive activation.\\u000a \\u000a \\u000a Methods: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters and were tested for their responses to subcutaneous\\u000a formalin injection into the hindpaw. Saline, midazolam (1 to 100 µg), AP-5 (1 to 30 µg),

  11. Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist ‘CJ17,493’

    Microsoft Academic Search

    Yuji Shishido; Hiroaki Wakabayashi; Hiroki Koike; Naomi Ueno; Seiji Nukui; Tatsuya Yamagishi; Yoshinori Murata; Fumiharu Naganeo; Mayumi Mizutani; Kaoru Shimada; Yoshiko Fujiwara; Ayano Sakakibara; Osamu Suga; Rinko Kusano; Satoko Ueda; Yoshihito Kanai; Megumi Tsuchiya; Kunio Satake

    2008-01-01

    A novel central nervous system (CNS) selective neurokinin-1 (NK1) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine ‘CJ-17,493’ (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (Ki=0.2nM) for the human NK1 receptor in IM-9 cells, potent activity in the [Sar9, Met(O2)11]SP-induced gerbil tapping model (ED50=0.04mg\\/kg, sc) and in the ferret cisplatin

  12. Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines

    Microsoft Academic Search

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

    2009-01-01

    Based on the definition of a 5-HT4 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-HT4 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 [3H]GR113808 (1) as

  13. Darifenacin: a muscarinic M3-selective receptor antagonist for the treatment of overactive bladder.

    PubMed

    Zinner, Norman

    2007-03-01

    Darifenacin is a novel, muscarinic M(3)-selective receptor antagonist with up to 59-fold selectivity for M(3) receptors compared with other muscarinic receptor subtypes and a low relative affinity for M(1) and M(2) receptors. This profile may explain its clinical efficacy in overactive bladder (OAB), the observed absence of adverse effects on cognitive function and reduced cardiovascular risks. Large-scale clinical trials have confirmed that darifenacin 7.5 and 15 mg/day provide rapid and meaningful improvement across a range of OAB symptoms, but with CNS and cardiac adverse event rates comparable to placebo. On this basis, darifenacin seems to meet the standard for an effective OAB pharmacotherapy that is well-tolerated and, more importantly, minimises the risk of safety-related adverse effects. PMID:17309345

  14. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites.

    PubMed

    Ekins, Sean; Chang, Cheng; Mani, Sridhar; Krasowski, Matthew D; Reschly, Erica J; Iyer, Manisha; Kholodovych, Vladyslav; Ai, Ni; Welsh, William J; Sinz, Michael; Swaan, Peter W; Patel, Rachana; Bachmann, Kenneth

    2007-09-01

    The pregnane X receptor (PXR) is an important transcriptional regulator of the expression of xenobiotic metabolism and transporter genes. The receptor is promiscuous, binding many structural classes of molecules that act as agonists at the ligand-binding domain, triggering up-regulation of genes, increasing the metabolism and excretion of therapeutic agents, and causing drug-drug interactions. It has been suggested that human PXR antagonists represent a means to counteract such interactions. Several azoles have been hypothesized to bind the activation function-2 (AF-2) surface on the exterior of PXR when agonists are concurrently bound in the ligand-binding domain. In the present study, we have derived novel computational models for PXR agonists using different series of imidazoles, steroids, and a set of diverse molecules with experimental PXR agonist binding data. We have additionally defined a novel pharmacophore for the steroidal agonist site. All agonist pharmacophores showed that hydrophobic features are predominant. In contrast, a qualitative comparison with the corresponding PXR antagonist pharmacophore models using azoles and biphenyls showed that they are smaller and hydrophobic with increased emphasis on hydrogen bonding features. Azole antagonists were docked into a proposed hydrophobic binding pocket on the outer surface at the AF-2 site and fitted comfortably, making interactions with key amino acids involved in charge clamping. Combining computational and experimental data for different classes of molecules provided strong evidence for agonists and antagonists binding distinct regions on PXR. These observations bear significant implications for future discovery of molecules that are more selective and potent antagonists. PMID:17576789

  15. Antitumor activity of neurokinin-1 receptor antagonists in MG-63 human osteosarcoma xenografts.

    PubMed

    Muñoz, Miguel; Berger, Michael; Rosso, Marisa; Gonzalez-Ortega, Ana; Carranza, Andrés; Coveñas, Rafael

    2014-01-01

    Osteosarcoma is a highly malignant bone tumor in children and adolescents. Aprepitant is a selective high?affinity antagonist of the human neurokinin?1 (NK?1) receptor (NK1R) with robust antitumor activity. No data exist on the presence of NK1R in osteosarcoma and whether this tumor responds to NK1R antagonists. Here, we analyzed the expression of NK1R in the human osteosarcoma cell line MG-63 with western blot analysis and PCR and found significant expression both at the protein and mRNA levels. We further studied the growth inhibitory capacity of aprepitant and other NK1R antagonists on MG-63 in vitro using an MTS cytotoxicity assay and DAPI staining. All antagonists induced tumor growth inhibition and apoptosis. Synergism was observed for the combination of L-733,060 with common cytostatic drugs in MG-63, but not in non-malignant HEK293 cells. Pretreatment of HEK293 with L-733,060 prior to exposure to cytostatic drugs partially protected HEK293 cells from inhibition by these drugs. Furthermore, nanomolar concentrations of substance P (SP), the natural ligand of the NK1R, increased the growth rate of MG?63 cells and micromolar concentrations of aprepitant inhibited SP-induced growth in a dose?dependent manner. In vivo, a xenograft for MG-63 was created in nude mice and treated with peritumoral s.c. injections of fosaprepitant, which resulted in a significant reduction of tumor volume. Collectively, we demonstrated for the first time that the NK1R is expressed in human osteosarcoma cell line MG?63 and that this receptor can be targeted with NK1R antagonists both in vitro as well as in vivo. PMID:24190675

  16. Chemical function based pharmacophore generation of endothelin-A selective receptor antagonists.

    PubMed

    Funk, Oliver F; Kettmann, Viktor; Drimal, Jan; Langer, Thierry

    2004-05-20

    Both quantitative and qualitative chemical function based pharmacophore models of endothelin-A (ET(A)) selective receptor antagonists were generated by using the two algorithms HypoGen and HipHop, respectively, which are implemented in the Catalyst molecular modeling software. The input for HypoGen is a training set of 18 ET(A) antagonists exhibiting IC(50) values ranging between 0.19 nM and 67 microM. The best output hypothesis consists of five features: two hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI) function. The highest scoring Hip Hop model consists of six features: three hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI). It is the result of an input of three highly active, selective, and structurally diverse ET(A) antagonists. The predictive power of the quantitative model could be approved by using a test set of 30 compounds, whose activity values spread over 6 orders of magnitude. The two pharmacophores were tested according to their ability to extract known endothelin antagonists from the 3D molecular structure database of Derwent's World Drug Index. Thereby the main part of selective ET(A) antagonistic entries was detected by the two hypotheses. Furthermore, the pharmacophores were used to screen the Maybridge database. Six compounds were chosen from the output hit lists for in vitro testing of their ability to displace endothelin-1 from its receptor. Two of these are new potential lead compounds because they are structurally novel and exhibit satisfactory activity in the binding assay. PMID:15139753

  17. Preclinical and clinical characterization of the selective 5-HT1A receptor antagonist DU-125530 for antidepressant treatment

    PubMed Central

    Scorza, MC; Lladó-Pelfort, L; Oller, S; Cortés, R; Puigdemont, D; Portella, MJ; Pérez-Egea, R; Alvarez, E; Celada, P; Pérez, V; Artigas, F

    2012-01-01

    BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT1A autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT1A receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed ?-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT1A autoreceptors. However, it is unclear whether 5-HT1A receptor antagonists not discriminating between pre- and post-synaptic 5-HT1A receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT1A receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT1A receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT1A receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT1A receptor antagonist. However, blockade of post-synaptic 5- HT1A receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function. PMID:22050051

  18. A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor ? chains

    PubMed Central

    England, Bruce P.; Balasubramanian, Palaniappan; Uings, Iain; Bethell, Sue; Chen, Min-Jia; Schatz, Peter J.; Yin, Qun; Chen, Yao-Fen; Whitehorn, Erik A.; Tsavaler, Alexander; Martens, Christine L.; Barrett, Ronald W.; McKinnon, Murray

    2000-01-01

    Two series of peptides that specifically bind to the extracellular domain of the ? chain of the human interleukin-5 receptor (IL-5R?), but share no primary sequence homology to IL-5, were identified from libraries of random recombinant peptides. Affinity maturation procedures generated a 19-aa peptide that binds to the IL-5 receptor ?/? heterodimer complex with an affinity equal to that of IL-5 and is a potent and specific antagonist of IL-5 activity in a human eosinophil adhesion assay. The active form of the peptide is a disulfide-crosslinked dimer that forms spontaneously in solution. Gel filtration analysis, receptor-binding studies, and analytical ultracentrifugation reveal that the dimeric peptide binds simultaneously to two receptor ? chains in solution. Furthermore, the dimer peptide, but not IL-5, can activate a chimeric receptor consisting of the IL-5R? extracellular domain fused to the intracellular domain of the epidermal growth factor receptor, thus demonstrating that the peptide also promotes receptor dimerization in a cellular context. The functional antagonism produced by the bivalent interaction of the dimeric peptide with two IL-5R ? chains represents a distinctive mechanism for the antagonism of cytokines that use heteromeric receptors. PMID:10823900

  19. A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor alpha chains.

    PubMed

    England, B P; Balasubramanian, P; Uings, I; Bethell, S; Chen, M J; Schatz, P J; Yin, Q; Chen, Y F; Whitehorn, E A; Tsavaler, A; Martens, C L; Barrett, R W; McKinnon, M

    2000-06-01

    Two series of peptides that specifically bind to the extracellular domain of the alpha chain of the human interleukin-5 receptor (IL-5Ralpha), but share no primary sequence homology to IL-5, were identified from libraries of random recombinant peptides. Affinity maturation procedures generated a 19-aa peptide that binds to the IL-5 receptor alpha/beta heterodimer complex with an affinity equal to that of IL-5 and is a potent and specific antagonist of IL-5 activity in a human eosinophil adhesion assay. The active form of the peptide is a disulfide-crosslinked dimer that forms spontaneously in solution. Gel filtration analysis, receptor-binding studies, and analytical ultracentrifugation reveal that the dimeric peptide binds simultaneously to two receptor alpha chains in solution. Furthermore, the dimer peptide, but not IL-5, can activate a chimeric receptor consisting of the IL-5Ralpha extracellular domain fused to the intracellular domain of the epidermal growth factor receptor, thus demonstrating that the peptide also promotes receptor dimerization in a cellular context. The functional antagonism produced by the bivalent interaction of the dimeric peptide with two IL-5R alpha chains represents a distinctive mechanism for the antagonism of cytokines that use heteromeric receptors. PMID:10823900

  20. Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction

    PubMed Central

    Andersson, Karl-Erik; Campeau, Lysanne; Olshansky, Brian

    2011-01-01

    Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life-long. Antimuscarinics are generally considered to be ‘safe’ drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible. PMID:21595741

  1. NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury

    PubMed Central

    Li, Yang; Liu, Yong; Peng, XiangPing; Liu, Wei; Zhao, FeiYan; Feng, DanDan; Han, JianZhong; Huang, YanHong; Luo, SiWei; Li, Lian; Yue, Shao Jie; Cheng, QingMei; Huang, XiaoTing; Luo, ZiQiang

    2015-01-01

    Background Glutamate is a major neurotransmitter in the central nervous system (CNS). Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. Recently, NMDAR has been reported to be found in the lungs. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycin-induced lung injury mice. Methods C57BL/6 mice were intratracheally injected with bleomycin (BLM) to induce lung injury. Mice were randomized to receive saline, memantine (Me), BLM, BLM plus Me. Lungs and BALF were harvested on day 3 or 7 for further evaluation. Results BLM caused leukocyte infiltration, pulmonary edema and increase in cytokines, and imposed significant oxidative stress (MDA as a marker) in lungs. Memantine significantly mitigated the oxidative stress, lung inflammatory response and acute lung injury caused by BLM. Moreover, activation of NMDAR enhances CD11b expression on neutrophils. Conclusions Memantine mitigates oxidative stress, lung inflammatory response and acute lung injury in BLM challenged mice. PMID:25942563

  2. The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors.

    PubMed

    Wicke, K; Garcia-Ladona, J

    2001-07-20

    Recent studies have fueled the interest in dopamine D3 receptor antagonists and partial agonist for the treatment of psychosis and drug abuse, respectively. N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide (BP 897) is a dopamine D3 receptor selective ligand recently described as partial agonist with potential effects on drug-dependence. The aim of the present study was to determine both the functional activity of BP 897 at human dopamine D3 receptors expressed in Chinese hamster ovary (CHO) cells and in an electrophysiological in vivo model of dopaminergic activity. BP 897 failed to stimulate the human dopamine D3 receptor and showed antagonistic effects (cpIC(50)=9.51) in a [(35)S]GTPgammaS binding assay in cells expressing the human dopamine D3 receptor. In vivo, BP 897 up to 8.2 mg/kg, i.v., had no agonistic effects on firing rate of substantia nigra dopaminergic neurons and antagonized the quinpirole-induced inhibition of firing (DID(50)=1.1 mg/kg). Our data demonstrate that BP 897 acts, in vivo and in vitro, as a dopamine D3 receptor antagonist. PMID:11476753

  3. Estrogen receptor (ER) agonists and androgen receptor (AR) antagonists in effluents from Norwegian North Sea oil production platforms.

    PubMed

    Tollefsen, Knut-Erik; Harman, Christopher; Smith, Andy; Thomas, Kevin V

    2007-03-01

    The in vitro estrogen receptor (ER) agonist and androgen receptor (AR) antagonist potencies of offshore produced water effluents collected from the Norwegian Sector were determined using recombinant yeast estrogen and androgen screens. Solid phase extraction (SPE) concentrates of the effluents showed E2 agonist activities similar to those previously reported for the United Kingdom (UK) Continental Shelf (<0.1-4 ng E2 L(-1)). No activity was detected in the filtered oil droplets suggesting that produced water ER activity is primarily associated with the dissolved phase. Targeted analysis for methyl- to nonyl-substituted alkylphenol isomers show the occurrence of known ER agonists in the analysed samples. For the first time, AR antagonists were detected in both the dissolved and oil associated phase at concentrations of between 20 and 8000 microg of flutamide equivalents L(-1). The identity of the AR antagonists is unknown, however this represents a significant input into the marine environment of unknown compounds that exert a known biological effect. It is recommended that further analysis using techniques such as bioassay-directed analysis is performed to identify the compounds/groups of compounds that are responsible in order to improve the assessment of the risk posed by produced water discharges to the marine environment. PMID:17258235

  4. 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. PMID:19261477

  5. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

    PubMed

    Wong, Gilbert Y; Gavva, Narender R

    2009-04-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

  6. 3D-pharmacophere models for CC chemokine receptor 1 antagonists.

    PubMed

    Liu, Yixi; Andre, Philippe; Wei, Jing; Zhao, Kang

    2009-07-01

    The CC Chemokine Receptor 1 (CCR1) is closely related to various chronic inflammatory diseases like rheumatoid arthritis and multiple sclerosis, and plays a crucial role in transplant rejection. Inhibiting its activity with CCR1 antagonists has been proved to be effective in preventing some diseases. A number of in vivo experiments have been carried out to shed light on the underlying mechanism of the interactions between the CCR1 and its ligands. However, their conclusions are still controversial. In this study, ligand-based computational drug design is applied as a new and effective way to study the structure-activity relationship of CCR1 antagonists. Three-dimensional pharmacophore models were generated for CCR1 antagonists, using both HypoGen and HipHop algorithms in Catalyst software. Two optimal pharmacophore models were defined through careful qualification processes. Both of them have four features: one hydrogen-bond acceptor, one positive ionable and two hydrophobic groups. Additional information was obtained through comparison between the two models. Our results can be valuable tools for the discovery and development of specific, highly potent CCR1 antagonists. For Supplement material, please see the online version of the article. PMID:19689388

  7. Non-peptide angiotensin II receptor antagonists: chemical feature based pharmacophore identification.

    PubMed

    Krovat, Eva M; Langer, Thierry

    2003-02-27

    Chemical feature based pharmacophore models were elaborated for angiotensin II receptor subtype 1 (AT(1)) antagonists using both a quantitative and a qualitative approach (Catalyst HypoGen and HipHop algorithms, respectively). The training sets for quantitative model generation consisted of 25 selective AT(1) antagonists exhibiting IC(50) values ranging from 1.3 nM to 150 microM. Additionally, a qualitative pharmacophore hypothesis was derived from multiconformational structure models of the two highly active AT(1) antagonists 4u (IC(50) = 0.2 nM) and 3k (IC(50) = 0.7 nM). In the case of the quantitative model, the best pharmacophore hypothesis consisted of a five-features model (Hypo1: seven points, one hydrophobic aromatic, one hydrophobic aliphatic, a hydrogen bond acceptor, a negative ionizable function, and an aromatic plane function). The best qualitative model consisted of seven features (Hypo2: 11 points, two aromatic rings, two hydrogen bond acceptors, a negative ionizable function, and two hydrophobic functions). The obtained pharmacophore models were validated on a wide set of test molecules. They were shown to be able to identify a range of highly potent AT(1) antagonists, among those a number of recently launched drugs and some candidates presently undergoing clinical tests and/or development phases. The results of our study provide confidence for the utility of the selected chemical feature based pharmacophore models to retrieve structurally diverse compounds with desired biological activity by virtual screening. PMID:12593652

  8. Correlation between log POCT/H2O and pKB estimates for a series of muscarinic and histamine H2-receptor antagonists.

    PubMed Central

    Shankley, N. P.; Black, J. W.; Ganellin, C. R.; Mitchell, R. C.

    1988-01-01

    1. With histamine used as agonist, pKB values were estimated for seventeen histamine H2-receptor antagonists on assays involving acid secretion by the mouse isolated stomach and contraction frequency of the guinea-pig right atrium. 2. With the exception of oxmetidine, SK&F 94,826 and SK&F 94,206 on the right atrium assay, the compounds behaved as simple competitive antagonists on both assays. Although the former three compounds produced concentration-dependent, parallel, displacement of the histamine concentration-effect curves, subsequent analysis indicated Schild plot slope parameters significantly less than unity. However, the application of a combined dose-ratio analysis indicated that their antagonistic behaviour did not differ from expectations for simple competition at dose-ratios of approximately 20, and pKB values were estimated on this basis. 3. In accordance with previously reported data, pKB values were found to be consistently lower on the stomach than atrial assays. The pKB value for tiotidine was underestimated to the same extent on the stomach assay when impromidine was used as agonist. 4. The removal of the serosal muscle from the mouse stomach, achieved by using an isolated, perfused, mucosal sheet preparation, did not significantly affect the underestimation of the pKB value for metiamide. 5. Linear regressional analysis indicated a significant, positive, correlation between lipophilicity (log POCT/H2O) of the antagonists and the degree of antagonist pKB value underestimation on the gastric secretion assay. PMID:2900037

  9. ?CCT, AN ANTAGONIST SELECTIVE FOR ?1 GABAA RECEPTORS, REVERSES DIAZEPAM WITHDRAWAL-INDUCED ANXIETY IN RATS

    PubMed Central

    Divljakovi?, Jovana; Mili?, Marija; Namjoshi, Ojas A.; Tiruveedhula, Veera V.; Timi?, Tamara; Cook, James M.; Savi?, Miroslav M.

    2012-01-01

    The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABAA receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABAA receptors containing ?1 subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential ?1-subunit selective antagonist ?CCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10 mg/kg) or ?CCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABAA receptors may reverse the withdrawal-induced anxiety involves the ?1 subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABAA receptors. PMID:23149168

  10. Augmentation of antipsychotic-induced neurochemical changes by the NK3 receptor antagonist talnetant (SB-223412).

    PubMed

    de la Flor, Raúl; Dawson, Lee A

    2009-02-01

    Neurokinin-3 (NK(3)) receptor distribution and its modulatory influence on dopaminergic and noradrenergic neurotransmission have lead to the hypothesis that NK(3) receptor antagonists may be a valid target to ameliorate the symptomatology of schizophrenia. This hypothesis has gained some clinical support as the selective NK(3) receptor antagonist osanetant has shown efficacy in schizophrenic patients. Talnetant (SB-223412) is a potent and selective NK(3) receptor antagonist able to modulate monoaminergic neurotransmission in both cortical and subcortical brain structures. Here we have used in vivo microdialysis to investigate the adjunctive effects of talnetant (10 and 30 mg/kg; i.p.) on typical (i.e. haloperidol, 0.3 and 1 mg/kg; i.p.) and atypical (i.e. risperidone, 0.3 and 1 mg/kg; i.p.) antipsychotic drug-induced changes in monoaminergic neurotransmission in forebrain structures of the guinea pig. As seen previously talnetant, produced a dose dependent increase in extracellular levels of both dopamine (DA) and norepinephrine (NE) in both prefrontal cortex (PFC) and hippocampus in a similar manner to the atypical risperidone. Combination studies revealed an additive effect of talnetant on risperidone-induced changes in both NE and DA levels in the PFC but not the hippocampus. Furthermore, addition of talnetant converted the neurochemical profile of the typical antipsychotic, haloperidol, to a profile more akin to that induced by an atypical antipsychotic. These data suggest that addition of talnetant to antipsychotic drugs may facilitate monoaminergic neurotransmission and hence potentially improve their clinical efficacy. PMID:18822303

  11. MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats.

    PubMed

    Bell, Ian M; Stump, Craig A; Gallicchio, Steven N; Staas, Donnette D; Zartman, C Blair; Moore, Eric L; Sain, Nova; Urban, Mark; Bruno, Joseph G; Calamari, Amy; Kemmerer, Amanda L; Mosser, Scott D; Fandozzi, Christine; White, Rebecca B; Zrada, Matthew M; Selnick, Harold G; Graham, Samuel L; Vacca, Joseph P; Kane, Stefanie A; Salvatore, Christopher A

    2012-06-15

    Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo. PMID:22607672

  12. 5-HT antagonists and blockade of neuronal (5-HT) receptors on ganglion cells.

    PubMed

    Nash, H L; Wallis, D I; Ash, G

    1984-01-01

    Potential changes in superior cervical ganglion cells evoked by 5-HT or the nicotinic agonist, dimethyl-phenyl piperazinium (DMPP), were recorded using the sucrose-gap method and a number of putative 5-HT antagonists tested for potency and selectivity. Selective blockade of 5-HT responses was produced by 5-HT itself and, in increasing order of potency, by cocaine, metoclopramide and quipazine. A non-selective blockade was observed with bufotenine and d-tubocurarine. Substances which had no effect on 5-HT responses included methysergide and other compounds related to LSD, cinanserin, cyproheptadine, phenylbiguanide and morphine. The results provide further information about the 5-HT receptor on sympathetic ganglion cells and support the view that this receptor is distinct from neuronal receptors in the myenteric plexus and on cholinergic nerve terminals. PMID:6149168

  13. Modified 2'-ribose small RNAs function as Toll-like receptor-7/8 antagonists.

    PubMed

    Sioud, Mouldy

    2015-01-01

    A subset of Toll-like receptors (TLRs) senses microbial nucleic acids in endosomal compartments. Furthermore, under certain conditions TLRs can recognize self-RNAs leading to the induction and/or perpetuation of inflammatory diseases. Recent studies have shown that the incorporation of modified nucleotides into small interfering RNA suppressed unwanted immunostimulation. Interestingly, RNA harboring 2'-ribose modifications, particularly 2'-O-methyl not only evaded immune activation but also suppressed TLR signaling triggered in-trans by immunostimulatory RNAs. This new generation of TLR antagonists may have utility as inhibitors of pathogenic inflammatory reactions mediated by TLR activation. Beyond their structural role, natural modifications in native eukaryotic RNAs may function as endogenous TLR antagonists as well. This chapter describes the characterization of short synthetic small RNAs that suppress immunostimulatory activity in-trans. PMID:25319669

  14. High resolution NMR conformational studies of new bivalent NOP receptor antagonists in model membrane systems.

    PubMed

    Borioni, Anna; Bastanzio, Giuditta; Delfini, Maurizio; Mustazza, Carlo; Sciubba, Fabio; Tatti, Massimo; Del Giudice, Maria Rosaria

    2011-02-01

    The interaction of new bivalent NOP receptor antagonists with dodecyl phosphatidylcholine micelles and DMPC/cholesterol liposomes was investigated in solution by high resolution NMR. The ligands are structurally related to the NOP antagonist JTC-801 plus a propanediamine or heptanediamine spacer between the pharmacophoric units. Ligand internuclear distances were derived from 2D NOESY data and applied to molecular modelling calculations as conformational restraints. NMR experiments on micelles evidenced that the ligands closely approached the micelles but gave no hints on the preferential conformations of the interacting ligands. Results from NMR experiments in the presence of liposomes clearly indicated that both ligands strongly interacted with the bilayer assuming a preferential folded conformation with the quinoline arms superimposing on each other. The finding suggested that these strongly lipophilic pharmacophores could localize in the native receptorial membrane in the form of a depot, gaining access to the recognition site via the lipid bilayer. PMID:21211814

  15. Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms.

    PubMed

    Schiedel, Anke C; Lacher, Svenja K; Linnemann, Carsten; Knolle, Percy A; Müller, Christa E

    2013-09-01

    The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutinin-stimulated human peripheral blood lymphocytes (PBL), and Jurkat T cells were investigated. Real-time PCR measurements confirmed the presence of all four AR subtypes on the investigated cells, although at different expression levels. A2A ARs were predominantly expressed in PBL and further upregulated upon stimulation, while malignant Jurkat T cells showed high expression levels of A1, A2A, and A2B ARs. Cell proliferation was measured by [(3)H]-thymidine incorporation assays. Several ligands, including the subtype-selective agonists CPA (A1), BAY60-6583 (A2B), and IB-MECA (A3), and the antagonists PSB-36 (A1), MSX-2 (A2A), and PSB-10 (A3) significantly inhibited cell proliferation at micromolar concentrations, which were about three orders of magnitude higher than their AR affinities. In contrast, further investigated AR ligands, including the agonists NECA (nonselective) and CGS21680 (A2A), and the antagonists preladenant (SCH-420814, A2A), PSB-1115 (A2B), and PSB-603 (A2B) showed no or only minor effects on lymphocyte proliferation. The anti-proliferative effects of the AR agonists could not be blocked by the corresponding antagonists. The non-selective AR antagonist caffeine stimulated phytohemagglutinin-activated PBL with an EC50 value of 104 ?M. This is the first study to compare a complete set of commonly used AR ligands for all subtypes on lymphocyte proliferation. Our results strongly suggest that these compounds induce an inhibition of lymphocyte proliferation and cell death through AR-independent mechanisms. PMID:23359122

  16. Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms.

    PubMed

    Dubocovich, M L; Yun, K; Al-Ghoul, W M; Benloucif, S; Masana, M I

    1998-09-01

    This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 microg/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 microg/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 microg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 microg/mouse, s.c.) nor luzindole (300 microg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 microg melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders. PMID:9737724

  17. Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain

    Microsoft Academic Search

    Peter K Zahn; Eric Umali; Timothy J Brennan

    1998-01-01

    Evidence indicates that excitatory amino acids (EAAs) like glutamate and aspartate are important in the processing of nociceptive information in the dorsal horn of the spinal cord. Recently, the role of particular EAA receptors in pain transmission and facilitated pain states has been examined utilizing spinal administration of specific receptor antagonists. Most investigators have studied the involvement of N-methyl-d-aspartate (NMDA)

  18. NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats

    Microsoft Academic Search

    John E. Kelsey; Stephen D. Mague; Reyna S. Pijanowski; Ryan C. Harris; Nancy W. Kleckner; Russell T. Matthews

    2004-01-01

    Rationale and objectives To test the hypothesis that excess glutamatergic transmission at NMDA receptors may contribute to the pathogenesis of Parkinson’s disease (PD), we examined the effects of various NMDA receptor antagonists on a recently developed rat model of PD. Methods Following unilateral injections of 12 µg 6-OHDA into the medial forebrain bundle of male Long Evans rats, stepping with both

  19. PG01037, a novel dopamine D3 receptor antagonist, inhibits the effects of methamphetamine in rats

    PubMed Central

    Higley, Amanda E; Spiller, Krista; Grundt, Peter; Newman, Amy Hauck; Kiefer, Stephen W; Xi, Zheng-Xiong; Gardner, Eliot L

    2013-01-01

    Our previous studies have shown that the selective dopamine D3 receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D3 receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30 mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D3 antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D3 antagonists in the treatment of methamphetamine addiction. PMID:20142301

  20. Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action

    PubMed Central

    Aldrich, Jane V.; Patkar, Kshitij A.; McLaughlin, Jay P.

    2009-01-01

    The cyclic peptide zyklophin {[N-benzylTyr1,cyclo(D-Asp5,Dap8)-dynorphin A-(1–11)NH2, Patkar KA, et al. (2005) J Med Chem 48: 4500–4503} is a selective peptide kappa opioid receptor (KOR) antagonist that shows activity following systemic administration. Systemic (1–3 mg/kg s.c.) as well as central (0.3–3 nmol intracerebroventricular, i.c.v.) administration of this peptide dose-dependently antagonizes the antinociception induced by the selective KOR agonist U50,488 in C57BL/6J mice tested in the 55 °C warm water tail withdrawal assay. Zyklophin administration had no effect on morphine- or SNC-80-mediated antinociception, suggesting that zyklophin selectively antagonizes KOR in vivo. Additionally, the antagonism of antinociception induced by centrally (i.c.v.) administered U50,488 following peripheral administration of zyklophin strongly suggests that the peptide crosses the blood-brain barrier to antagonize KOR in the CNS. Most importantly, the antagonist activity of zyklophin (3 mg/kg s.c.) lasts less than 12 h, which contrasts sharply with the exceptionally long duration of antagonism reported for the established small-molecule selective KOR antagonists such as nor-binaltorphimine (nor-BNI) that last weeks after a single administration. Systemically administered zyklophin (3 mg/kg s.c.) also prevented stress-induced reinstatement of cocaine-seeking behavior in a conditioned place preference assay. In conclusion, the peptide zyklophin is a KOR-selective antagonist that exhibits the desired shorter duration of action, and represents a significant advance in the development of KOR-selective antagonists. PMID:19841255

  1. Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action.

    PubMed

    Aldrich, Jane V; Patkar, Kshitij A; McLaughlin, Jay P

    2009-10-27

    The cyclic peptide zyklophin {[N-benzylTyr(1),cyclo(D-Asp(5),Dap(8))-dynorphin A-(1-11)NH(2), Patkar KA, et al. (2005) J Med Chem 48: 4500-4503} is a selective peptide kappa opioid receptor (KOR) antagonist that shows activity following systemic administration. Systemic (1-3 mg/kg s.c.) as well as central (0.3-3 nmol intracerebroventricular, i.c.v.) administration of this peptide dose-dependently antagonizes the antinociception induced by the selective KOR agonist U50,488 in C57BL/6J mice tested in the 55 degrees C warm water tail withdrawal assay. Zyklophin administration had no effect on morphine- or SNC-80-mediated antinociception, suggesting that zyklophin selectively antagonizes KOR in vivo. Additionally, the antagonism of antinociception induced by centrally (i.c.v.) administered U50,488 following peripheral administration of zyklophin strongly suggests that the peptide crosses the blood-brain barrier to antagonize KOR in the CNS. Most importantly, the antagonist activity of zyklophin (3 mg/kg s.c.) lasts less than 12 h, which contrasts sharply with the exceptionally long duration of antagonism reported for the established small-molecule selective KOR antagonists such as nor-binaltorphimine (nor-BNI) that last weeks after a single administration. Systemically administered zyklophin (3 mg/kg s.c.) also prevented stress-induced reinstatement of cocaine-seeking behavior in a conditioned place preference assay. In conclusion, the peptide zyklophin is a KOR-selective antagonist that exhibits the desired shorter duration of action, and represents a significant advance in the development of KOR-selective antagonists. PMID:19841255

  2. Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia.

    PubMed

    Roecker, Anthony J; Reger, Thomas S; Mattern, M Christa; Mercer, Swati P; Bergman, Jeffrey M; Schreier, John D; Cube, Rowena V; Cox, Christopher D; Li, Dansu; Lemaire, Wei; Bruno, Joseph G; Harrell, C Meacham; Garson, Susan L; Gotter, Anthony L; Fox, Steven V; Stevens, Joanne; Tannenbaum, Pamela L; Prueksaritanont, Thomayant; Cabalu, Tamara D; Cui, Donghui; Stellabott, Joyce; Hartman, George D; Young, Steven D; Winrow, Christopher J; Renger, John J; Coleman, Paul J

    2014-10-15

    Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species. PMID:25248679

  3. Orexin receptor type-1 antagonist SB-334867 inhibits the development of morphine analgesic tolerance in rats.

    PubMed

    Ranjbar-Slamloo, Yadollah; Azizi, Hossein; Fathollahi, Yaghoub; Semnanian, Saeed

    2012-05-01

    Herein the effect of orexin receptor type-1 antagonist SB-334867 on the development of tolerance to analgesic effects of morphine was studied in rats. To incite tolerance, morphine sulfate was injected intraperitoneally (i.p., 10mg/kg) once a day for 7 days. The tail flick test was used to evaluate antinociceptive effects of the morphine. A selective OxR1 receptor antagonist, SB-334867, was microinjected (i.c.v.) into the right cerebral ventricle (10 ?g/10 ?l) immediately before each morphine injection. Repeated morphine application resulted in tolerance to morphine analgesic effects as a decreasing trend during 7 days. Also, repeated administration of SB-334867 (i.c.v.) alone was without significant effect on the nociception as compared to control. Microinjection of SB-334867 prior to each morphine injection inhibited the development of tolerance, so that the analgesic effects of morphine were significantly higher in SB-334867 plus morphine treated rats than that of vehicle plus morphine treated ones on days 4-7. It is concluded that orexin receptor type-1 might be involved in the development of tolerance to morphine analgesic effects. PMID:22421510

  4. Phagocytosis of apoptotic and necrotic thymocytes is inhibited by PAF-receptor antagonists and affects LPS-induced COX2 expression in murine macrophages

    Microsoft Academic Search

    Soraya Imon de Oliveira; Patricia Dias Fernandes; João Gustavo P. Amarante Mendes; Sonia Jancar

    2006-01-01

    There is evidence that apoptotic cells and oxidized low density lipoprotein (oxLDL) particles have common ligands on their surface consisting of oxidized phospholipids which bind to scavenger receptors in macrophages leading to phagocytosis. Some effects of oxLDL binding to its receptor(s) were shown to be inhibited by Platelet Activating Factor (PAF)-receptor antagonists. Thus, we investigated the effect of PAF-receptor antagonists

  5. The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors

    PubMed Central

    Mang, Géraldine M.; Dürst, Thomas; Bürki, Hugo; Imobersteg, Stefan; Abramowski, Dorothee; Schuepbach, Edi; Hoyer, Daniel; Fendt, Markus; Gee, Christine E.

    2012-01-01

    Study Objectives: Orexin peptides activate orexin 1 and orexin 2 receptors (OX1R and OX2R), regulate locomotion and sleep-wake. The dual OX1R/OX2R antagonist almorexant reduces activity and promotes sleep in multiple species, including man. The relative contributions of the two receptors in locomotion and sleep/wake regulation were investigated in mice. Design: Mice lacking orexin receptors were used to determine the contribution of OX1R and OX2R to orexin A-induced locomotion and to almorexant-induced sleep. Setting: N/A. Patients or Participants: C57BL/6J mice and OX1R+/+, OX1R-/-, OX2R+/+, OX2R-/- and OX1R-/-/OX2R-/- mice. Interventions: Intracerebroventricular orexin A; oral dosing of almorexant. Measurements and Results: Almorexant attenuated orexin A-induced locomotion. As in other species, almorexant dose-dependently increased rapid eye movement sleep (REM) and nonREM sleep in mice. Almorexant and orexin A were ineffective in OX1R-/-/OX2R-/- mice. Both orexin A-induced locomotion and sleep induction by almorexant were absent in OX2R-/- mice. Interestingly, almorexant did not induce cataplexy in wild-type mice under conditions where cataplexy was seen in mice lacking orexins and in OX1R-/-/OX2R-/- mice. Almorexant dissociates very slowly from OX2R as measured functionally and in radioligand binding. Under non equilibrium conditions in vitro, almorexant was a dual antagonist whereas at equilibrium, almorexant became OX2R selective. Conclusions: In vivo, almorexant specifically inhibits the actions of orexin A. The two known orexin receptors mediate sleep induction by almorexant and orexin A-induced locomotion. However, OX2R activation mediates locomotion induction by orexin A and antagonism of OX2R is sufficient to promote sleep in mice. Citation: Mang GM; Dürst T; Bürki H; Imobersteg S; Abramowski D; Schuepbach E; Hoyer D; Fendt M; Gee CE. The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. SLEEP 2012;35(12):1625-1635. PMID:23204605

  6. Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist

    PubMed Central

    Vardanyan, Marina; Melemedjian, Ohannes K; Price, Theodore J; Ossipov, Michael H.; Lai, Josephine; Roberts, Ed; Boos, Terrence L.; Deschamps, Jeffrey R; Jacobson, Arthur E; Rice, Kenner C; Porreca, Frank

    2012-01-01

    Pancreatic pain resulting from chronic inflammation of the pancreas is often intractable and clinically difficult to manage with available analgesics reflecting the need for more effective therapies. Mechanisms underlying pancreatitis pain are not well understood. Here, the possibility that interleukin-6 (IL-6) may promote pancreatitis pain was investigated with TB-2-081 (3-O-formyl-20R,21-epoxyresibufogenin, EBRF), a small molecule IL-6 receptor antagonist that was semi-synthetically derived from natural sources. The potential activity and mechanism of TB-2-081 was investigated following induction of persistent pancreatitis using dibutyltin dichloride (DBTC) in rats. TB-2-081 displaces binding of IL-6 to the human recombinant soluble IL-6 receptor with apparent high affinity and inhibits IL-6 mediated cell growth. Systemic or oral, but not intrathecal, administration of TB-2-081 reversed DBTC-induced abdominal hypersensitivity in a dose- and time-dependent manner. IL-6 levels were significantly upregulated in the dorsal root ganglia (DRG) of rats with pancreatitis on day 6 after DBTC injection. IL-6 enhanced capsaicin-evoked release of calcitonin gene related peptide from cultured DRG neurons was blocked by TB-2-081. Our data demonstrate that TB-2-081 acts as a systemically available and orally active small molecule IL-6 receptor antagonist. TB-2-081 effectively reduces pancreatitis-induced pain through peripheral mechanisms that are likely due to (a) increased expression of IL-6 in the DRG and (b) IL-6-mediated sensitization of nociceptive neurons. The activity of TB-2-081 implicates an important role for IL-6 in sustaining pancreatitis pain. Strategies targeting IL-6 actions through small molecule antagonists may offer novel approaches to improve therapy of chronic pancreatitis and other chronic pain states. PMID:20599324

  7. Clinical and preclinical characterization of the histamine H(4) receptor antagonist JNJ-39758979.

    PubMed

    Thurmond, Robin L; Chen, Bin; Dunford, Paul J; Greenspan, Andrew J; Karlsson, Lars; La, David; Ward, Peter; Xu, Xie L

    2014-05-01

    The histamine H4 receptor (H(4)R) has been shown to have preclinical involvement in both inflammatory and pruritic responses. JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent and selective H(4)R antagonist with a Ki at the human receptor of 12.5 ± 2.6 nM and greater than 80-fold selectivity over other histamine receptors. The compound also exhibited excellent selectivity versus other targets. JNJ-39758979 showed dose-dependent activity in models of asthma and dermatitis consistent with other H(4)R antagonists. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile, supporting the clinical testing of the compound. An oral formulation of JNJ-39758979 was studied in a phase 1 human volunteer study to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated, with the exception of dose-dependent nausea, and no safety issues were noted in the phase 1 study. JNJ-39758979 exhibited good pharmacokinetics upon oral dosing with a plasma half-life of 124-157 hours after a single oral dose. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H4R was inhibited in vivo. In conclusion, JNJ-39758979 is a potent and selective H(4)R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans. PMID:24549371

  8. Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin.

    PubMed

    Nakamura, Hironori; Yokoyama, Haruko; Takayanagi, Risa; Yoshimoto, Koichi; Nakajima, Akihiro; Okuyama, Kiyoshi; Iwase, Osamu; Yamada, Yasuhiko

    2015-03-01

    5-HT3 receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t 1/2), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT3 receptor antagonists, as those effects are not based solely on the t 1/2 value. We theoretically evaluated the antiemetic effects of three 5-HT3 receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT3 receptor occupancy of serotonin. We estimated the 5-HT3 receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT3 receptor antagonist and the time course of concentration of serotonin near the 5-HT3 receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT3 receptor antagonist was evaluated based on the normal level of 5-HT3 receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT3 receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin. PMID:24470169

  9. In vitro and in vivo pharmacological characterization of the novel NK? receptor selective antagonist Netupitant.

    PubMed

    Rizzi, Anna; Campi, Barbara; Camarda, Valeria; Molinari, Stefano; Cantoreggi, Sergio; Regoli, Domenico; Pietra, Claudio; Calo', Girolamo

    2012-09-01

    The novel NK(1) receptor ligand Netupitant has been characterized in vitro and in vivo. In calcium mobilization studies CHO cells expressing the human NK receptors responded to a panel of agonists with the expected order of potency. In CHO NK(1) cells Netupitant concentration-dependently antagonized the stimulatory effects of substance P (SP) showing insurmountable antagonism (pK(B) 8.87). In cells expressing NK(2) or NK(3) receptors Netupitant was inactive. In the guinea pig ileum Netupitant concentration-dependently depressed the maximal response to SP (pK(B) 7.85) and, in functional washout experiments, displayed persistent (up to 5h) antagonist effects. In mice the intrathecal injection of SP elicited the typical scratching, biting and licking response that was dose-dependently inhibited by Netupitant given intraperitoneally in the 1-10mg/kg dose range. In gerbils, foot tapping behavior evoked by the intracerebroventricular injection of a NK(1) agonist was dose-dependently counteracted by Netupitant given intraperitoneally (ID(50) 1.5mg/kg) or orally (ID(50) 0.5mg/kg). In time course experiments in gerbils Netupitant displayed long lasting effects. In all the assays Aprepitant elicited similar effects as Netupitant. These results suggest that Netupitant behaves as a brain penetrant, orally active, potent and selective NK(1) antagonist. Thus this molecule can be useful for investigating the NK(1) receptor role in the control of central and peripheral functions. Netupitant has clinical potential in conditions such as chemotherapy induced nausea and vomiting, in which the blockade of NK(1) receptors has been demonstrated valuable for patients. PMID:22732666

  10. Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist

    PubMed Central

    Doble, A.; Girdlestone, D.; Piot, O.; Allam, D.; Betschart, J.; Boireau, A.; Dupuy, A.; Guérémy, C.; Ménager, J.; Zundel, J.L.; Blanchard, J.C.

    1992-01-01

    1 RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8-cd]isothiazole-1, 1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT2 receptors in the rat cerebral cortex (Ki = 50.0 pM). 2 RP 62203 is relatively selective for this sub-type of 5-hydroxytryptamine (5-HT) receptor, having lower affinity for the 5-HT1A receptor and very low affinity for the 5-HT3 receptor. RP 62203 displayed low to moderate affinity for ?1-adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3 In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (>6h) occupation of cortical 5-HT2 receptors (ID50 = 0.39 mg kg-1). 4 In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC50 of 7.76 nM. 5 The activity of neurones in the raphé and their responses to microiontophoretically applied 5-HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose-dependently blocked excitations evoked by 5-HT when administered at doses of 0.5–4.0 mg kg-1, i.p. In contrast, neither 5-HT-evoked depressions nor glutamate-evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg-1, i.p. 6 Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg-1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5-hydroxytryptophan (5-HTP). 7 The potency of RP 62203 was compared with that of three other 5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8 It is concluded that RP 62203 is a potent and selective antagonist at 5-HT2 receptors in the rodent central nervous system. PMID:1596688

  11. Oral efficacy of a leukotriene B4 receptor antagonist in colitic cotton-top tamarins

    Microsoft Academic Search

    D Fretland; T Sanderson; P Smith; L Adams; R Carson; J Fuhr; J Tanner; N Clapp

    1995-01-01

    Leukotriene B4 (LTB4) is a potent neutrophil activator and chemotaxin that is present in increased concentrations in the colonic tissue and rectal dialysates of acute ulcerative colitis patients. Cotton-top tamarins (CTTs) with confirmed active colitis were treated with the second generation LTB4 receptor antagonist, SC-53228 ((+)-(S)-7-[3-(2-cyclopropyl-methyl)-3-methoxy-4-[(methylamino) carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- propanoic acid), 20 mg\\/kg bodyweight by gavage, twice daily for 56 days. End

  12. Characterization by antagonists of P2-receptors mediating endothelium-dependent relaxation in the rat aorta

    Microsoft Academic Search

    Georg Hansmann; Ralph Bültmann; Florin Tuluc; Klaus Starke

    1997-01-01

    The receptors through which 2-methylthio ATP (MeSATP), adenosine 5?-O-(2-thiodiphosphate) (ADP?S), UTP and ATP elicit endothelium-dependent\\u000a relaxation of noradrenaline-precontracted rings of the rat aorta were characterized by means of a series of antagonists. The\\u000a acetylcholine-induced relaxation and the degradation of MeSATP, UTP and ATP were also studied.\\u000a \\u000a The potency of the nucleotides at producing relaxation decreased in the order MeSATP (EC50

  13. Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: systematic review of current evidence

    PubMed Central

    Ducharme, Francine M

    2003-01-01

    Objective To compare the safety and efficacy of anti-leukotrienes and inhaled glucocorticoids as monotherapy in people with asthma. Design Systematic review of randomised controlled trials comparing anti-leukotrienes with inhaled glucocorticoids for 28 days or more in children and adults. Main outcome measure Rate of exacerbations that required treatment with systemic glucocorticoids. Results 13 trials (12 in adults, one in children) met the inclusion criteria; all were in people with mild and moderate asthma. Leukotriene receptor antagonists were compared with inhaled glucocorticoids at a daily dose equivalent to 400-450 ?g beclometasone dipropionate. Patients treated with leukotriene receptor antagonists were 60% more likely to suffer an exacerbation requiring systemic glucocorticoids (relative risk 1.6, 95% confidence interval 1.2 to 2.2; number needed to treat 27, 13 to 81). A 130 ml greater improvement (80 ml to 170 ml) in forced expiratory volume in one second and a 19 l/min greater increase (14 l to 24 l) in morning peak expiratory flow rate were noted in favour of inhaled glucocorticoids. Differences in favour of inhaled glucocorticoids were also observed for nocturnal awakenings, use of rescue ?2 agonists, and days without symptoms. Risk of side effects was no different between groups, but leukotriene receptor antagonists were associated a 2.5-fold increase risk of withdrawals due to poor asthma control (relative risk 2.5, 1.8 to 3.5). Conclusions Inhaled glucocorticoids doses equivalent to 400 ?g/day beclometasone are more effective than leukotriene receptor antagonists in the treatment of adults with mild or moderate asthma. There is insufficient evidence to conclude on the efficacy of anti-leukotrienes in children. What is already known on this topicIn 2000 a Cochrane systematic review tentatively concluded that control of asthma was better in patients treated with inhaled glucocorticoids as single agents than with anti-leukotrienesThe 2002 Global Initiative for Asthma guidelines still classify the role of anti-leukotrienes as “under investigation”What this study addsAnti-leukotrienes as single agent are less effective than low doses of inhaled glucocorticoids for patients with mild and moderate persistent asthma PMID:12649233

  14. Simultaneous determination of hydrochlorothiazide and several angiotensin-II-receptor antagonists by capillary electrophoresis.

    PubMed

    Hillaert, S; Van den Bossche, W

    2003-02-26

    We have investigated the capability of the capillary zone electrophoretic (CZE) and micellar electrokinetic capillary chromatographic (MEKC) methods to simultaneously separate hydrochlorothiazide and six angiotensin-II-receptor antagonists (ARA-IIs): candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, and valsartan. The CZE and MEKC methods are suitable for the qualitative and quantitative determination of combined HCT/ARA-IIs in pharmaceutical formulations. Depending on the ARA-II, at least one of the two methods can be used for each combination. The two methods have been validated in terms of their linearity of response, reproducibility, and accuracy. PMID:12609672

  15. Know thy Sef: a novel class of feedback antagonists of receptor tyrosine kinase signaling.

    PubMed

    Ron, Dina; Fuchs, Yaron; Chorev, Dror S

    2008-01-01

    The strength and duration of intracellular signals must be precisely regulated, since inappropriate signaling can cause disease. Negative feedback mechanisms provide an effective means of controlling growth factor-mediated signaling, either by restricting the incoming signal or by inducing counter-regulatory mechanisms affecting signal propagation. Sef proteins represent a new class of feedback antagonists capable of regulating receptor tyrosine kinase signaling. The involvement of Sef in development, as well as in other biological processes, was demonstrated by biochemical and genetic approaches. PMID:18450498

  16. Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew)

    Microsoft Academic Search

    John A Rudd; Celine H. K Cheng; Robert J Naylor; Man P Ngan; Man K Wai

    1999-01-01

    The anti-emetic mechanism of action of fentanyl to inhibit nicotine (5 mg\\/kg, s.c.)-induced emesis was investigated in Suncus murinus. The anti-emetic action of fentanyl (40 ?g\\/kg, s.c.) was antagonised by the opioid receptor antagonists naltrexone (1 mg\\/kg, s.c.), naloxone (1 mg\\/kg, s.c.), M8008 (16S-methylcyprenorphine; 1 mg\\/kg, s.c.) and MR 2266 (5,9-diethyl-2-(3-furylmethyl)2?-hydroxy-7,7-benzomorphan; 1 mg\\/kg) but not by naloxone methylbromide (1 mg\\/kg,

  17. Unusual pyrimidine participation: efficient stereoselective synthesis of potent dual orexin receptor antagonist MK-6096.

    PubMed

    Chung, John Y L; Zhong, Yong-Li; Maloney, Kevin M; Reamer, Robert A; Moore, Jeffrey C; Strotman, Hallena; Kalinin, Alexei; Feng, Ronnie; Strotman, Neil A; Xiang, Bangping; Yasuda, Nobuyoshi

    2014-11-21

    An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described. PMID:25365229

  18. Spontaneous Gelation of a Novel Histamine H4 Receptor Antagonist in Aqueous Solution

    Microsoft Academic Search

    Alexey Popov; Magali B. Hickey; Rupa Hiremath; Matthew Peterson; Poe Ratanabanangkoon; Michele Rizzolio; Sara Waggener; Yuri Zimenkov

    Purpose  Low molecular weight hydrogelators typically require a stimulus such as heat, antisolvent, or pH adjustment to produce a gel.\\u000a This study examines gelation of a novel histamine H4 receptor antagonist that forms hydrogels spontaneously at room temperature.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  To elucidate the mechanism and structural moieties responsible for this unusual gelation, hydrogels were characterized by\\u000a rheology, optical microscopy, and XRD. SEM was

  19. A selective M1 and M3 receptor antagonist, penehyclidine hydrochloride, prevents postischemic LTP: involvement of NMDA receptors.

    PubMed

    Ma, Teng-Fei; Zhou, Li; Wang, Yun; Qin, Shou-Jun; Zhang, Yuan; Hu, Bin; Yan, Jing-Zhi; Ma, Xing; Zhou, Cheng-Hua; Gu, Shu-Ling

    2013-12-01

    Our previous and other studies have confirmed that a selective M1 and M3 receptor antagonist, Penehyclidine hydrochloride (PHC), has neuroprotection activity in cerebral ischemia. However, the precise mechanisms of protection of PHC are still elusive. In this study we analyzed PHC-mediated neuroprotection on a model of brain ischemia (oxygen and glucose deprivation), named postischemic LTP (i-LTP). We found that the activation of NMDA receptor was required for the induction of i-LTP. Compared with scopolamine, PHC could prevent it due to selectively blocking M1 receptor, not M2 receptor, to decrease NMDAR activation. Our findings further showed that the inhibition of SK2 channels occluded the prevention of PHC on NMDAR activation. Furthermore, we confirmed that PHC exerted its roles through directly disinhibition of SK2 channels by blocking M1 receptor and subsequent restricting PKC activation. Moreover, our studies further revealed the critical roles of SK2 channels in i-LTP. Thus, the mechanisms of PHC in brain protection may be involved in suppression of NMDAR by regulation of SK2 channels. Our results obtained in effects of PHC on i-LTP further provided a better understanding of the therapy strategy during stroke and identified potential therapeutic targets to prevent development of ischemia. PMID:23813456

  20. Identification and characterisation of SB366791, a potent and selective vanilloid receptor (VR1\\/TRPV1) antagonist

    Microsoft Academic Search

    M. J. Gunthorpe; H. K. Rami; J. C. Jerman; D. Smart; C. H. Gill; E. M. Soffin; S. Luis Hannan; S. C. Lappin; J. Egerton; G. D. Smith; A. Worby; L. Howett; D. Owen; S. Nasir; C. H. Davies; M. Thompson; P. A. Wyman; A. D. Randall; J. B. Davis

    2004-01-01

    Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by

  1. Effects of High Affinity Leptin Antagonist on Prolactin Receptor Deficient Male Mouse

    PubMed Central

    Carré, Nadège; Solomon, Gili; Gertler, Arieh; Binart, Nadine

    2014-01-01

    Hyperprolactinemia occurs during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL) induces the expression of orexigenic neuropeptide Y (NPY) in hypothalamic dorsomedial nucleus (DMH) leading to hyperphagia. Along this line prolactin receptor deficient (PRLR?/?) mice are resistant to obesity under high fat diet due to increased energy expenditure. As these mice have an altered food intake, our objective was to test whether leptin is responsible for these characteristics. PRLR?/? male mice and control littermates were injected subcutaneously every other day with 12 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 3 weeks. We tested the effect of PEG-SMLA on body weight, food intake and metabolic parameters. The antagonist led to a rapid increase in body weight (20%) but increased adipose mass in PEG-SMLA treated mice was less pronounced in PRLR?/? than in WT mice. Food intake of PEG-SMLA-injected animals increased during the first week period of the experiment but then declined to a similar level of the control animals during the second week. Interestingly, PRLR?/? mice were found to have the same bone volume than those of control mice although PEG-SMLA increased bone mass by 7% in both strains. In addition, PEG-SMLA led to insulin resistance and glucose intolerance as well as an altered lipid profile in treated mice. Altogether, these results suggest that PRLR?/? mice respond to leptin antagonist similarly to the control mice, indicating no interaction between the actions of the two hormones. PMID:24667351

  2. Effects of high affinity leptin antagonist on prolactin receptor deficient male mouse.

    PubMed

    Carré, Nadège; Solomon, Gili; Gertler, Arieh; Binart, Nadine

    2014-01-01

    Hyperprolactinemia occurs during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL) induces the expression of orexigenic neuropeptide Y (NPY) in hypothalamic dorsomedial nucleus (DMH) leading to hyperphagia. Along this line prolactin receptor deficient (PRLR-/-) mice are resistant to obesity under high fat diet due to increased energy expenditure. As these mice have an altered food intake, our objective was to test whether leptin is responsible for these characteristics. PRLR-/- male mice and control littermates were injected subcutaneously every other day with 12 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 3 weeks. We tested the effect of PEG-SMLA on body weight, food intake and metabolic parameters. The antagonist led to a rapid increase in body weight (20%) but increased adipose mass in PEG-SMLA treated mice was less pronounced in PRLR-/- than in WT mice. Food intake of PEG-SMLA-injected animals increased during the first week period of the experiment but then declined to a similar level of the control animals during the second week. Interestingly, PRLR-/- mice were found to have the same bone volume than those of control mice although PEG-SMLA increased bone mass by 7% in both strains. In addition, PEG-SMLA led to insulin resistance and glucose intolerance as well as an altered lipid profile in treated mice. Altogether, these results suggest that PRLR-/- mice respond to leptin antagonist similarly to the control mice, indicating no interaction between the actions of the two hormones. PMID:24667351

  3. Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H? receptor antagonists.

    PubMed

    Savall, Brad M; Chavez, Frank; Tays, Kevin; Dunford, Paul J; Cowden, Jeffery M; Hack, Michael D; Wolin, Ronald L; Thurmond, Robin L; Edwards, James P

    2014-03-27

    This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects. PMID:24495018

  4. Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.

    PubMed

    Nikolic, Katarina; Filipic, Slavica; Agbaba, Danica; Stark, Holger

    2014-07-01

    The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here. PMID:24836924

  5. Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat.

    PubMed

    Varga, Csaba; Horvath, Krisztina; Berko, Aniko; Thurmond, Robin L; Dunford, Paul J; Whittle, Brendan J R

    2005-10-17

    The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.o., b.i.d.) caused a dose-dependent reduction in macroscopic damage, inhibition of the TNBS-provoked elevation of both colonic myeloperoxidase and tumour necrosis factor-alpha (TNF-alpha), and a reduction in the histologically assessed increase in mucosal and submucosal thickness and neutrophil infiltration. JNJ 7777120 (100 mg/kg p.o., b.i.d.) likewise reduced the macroscopic injury and the increases in colonic myeloperoxidase and TNF-alpha levels. These findings indicate a pro-inflammatory role for the histamine H(4) receptor in this model and suggest a novel pharmacological approach to the treatment of colitis. PMID:16213481

  6. Design, Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ?1 GABAC Receptors.

    PubMed

    Gavande, Navnath; Kim, Hye-Lim; Doddareddy, Munikumar R; Johnston, Graham A R; Chebib, Mary; Hanrahan, Jane R

    2013-04-11

    The ?1 GABAC receptor is a ligand-gated chloride ion channel that shows promise as a therapeutic target for myopia, sleep disorders, memory and learning facilitation, and anxiety-related disorders. As such, there is a need for molecular probes to understand the role GABAC receptors play in physiological and pathological processes. To date, no labeled (either radioactive or fluorescent) GABAC selective ligand has been developed that can act as a marker for GABAC receptor visualization and localization studies. Herein, we report a series of fluorescent ligands containing different-sized linkers and fluorophores based around (S)-4-ACPBPA [(4-aminocyclopenten-1-yl)-butylphosphinic acid], a selective GABAC antagonist. One of these conjugates, (S)-4-ACPBPA-C5-BODIPY (13), displayed moderate potency (IC50 = 58.61 ?M) and selectivity (>100 times) for ?1 over ?1?2?2L GABAA receptors. These conjugates are novel lead agents for the development of more potent and selective fluorescent probes for studying the localization and function of GABAC receptors in living cells. PMID:24900684

  7. Potency enhancement of the ?-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif.

    PubMed

    Frankowski, Kevin J; Slauson, Stephen R; Lovell, Kimberly M; Phillips, Angela M; Streicher, John M; Zhou, Lei; Whipple, David A; Schoenen, Frank J; Prisinzano, Thomas E; Bohn, Laura M; Aubé, Jeffrey

    2015-07-15

    Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists. PMID:25593096

  8. Competitive receptor binding radioassay for US -1 and US -2 adrenergic agents

    SciTech Connect

    Hussain, M.N.; Culbreth, W.; Dalrymple, R.; Fung, C.; Ricks, C.

    1987-05-01

    A rapid and sensitive competitive receptor bonding assay for US -1 and US -2 adrenergic binding for adrenergic agents has been developed. The steps that are critical for the success of the assay are given in detail so that the assay can be set up in any routine laboratory with relative ease. The rationale behind the use of specific reagents is discussed. The assay requires microgram quantities of test compound, a radiolabeled specific US adrenergic antagonist (TH)dihydroalprenolol (DHA), and turkey erythrocyte US -1 and rat erythrocyte US -2 receptor membranes. Serial dilutions of sample are incubated with appropriate receptor membranes and DHA for 1 hr at room temperature. After equilibrium is attained, the bound radioligand is separated by rapid filtration under vacuum through Whatman GF/B filters. The amount of bound DHA trapped on the filter is inversely proportional to the degree of US -1 and US -2 adrenergic binding of the sample. Separation of bound from free radioligand by filtration permits rapid determination of a large number of samples. This assay quantitates and differentiates US -1 and US -2 adrenergic binding of synthetic adrenergic agents.

  9. Lipopolysaccharide and Raf-1 kinase regulate secretory interleukin-1 receptor antagonist gene expression by mutually antagonistic mechanisms.

    PubMed Central

    Guthridge, C J; Eidlen, D; Arend, W P; Gutierrez-Hartmann, A; Smith, M F

    1997-01-01

    Lipopolysaccharide (LPS) treatment of monocytic cells has been shown to activate the Raf-1/mitogen-activated protein kinase (MAPK) signaling pathway and to increase secretory interleukin-1 receptor antagonist (sIL-1Ra) gene expression. The significance of the activation of the Raf-1/MAPK signaling pathway to LPS regulation of sIL-1Ra gene expression, however, has not been determined. This study addresses the role of the Raf-1/MAPK signaling pathway in regulation of sIL-1Ra gene expression by LPS. Cotransfection of the murine macrophage cell line RAW 264.7 with a 294-bp sIL-1Ra promoter/luciferase construct (pRA-294-luc) and a constitutively active Raf-1 kinase expression vector (pRSV-Raf-BXB) resulted in induction of sIL-1Ra promoter activity, indicating that Raf-1, like LPS, can regulate sIL-1Ra promoter activity. An in vitro MAPK analysis indicated that both LPS treatment and pRSV-Raf-BXB transfection of RAW 264.7 cells increases p42 MAPK activity. An in vitro Raf-1 kinase assay, however, failed to detect LPS-induced Raf-1 kinase activity in RAW 264.7 cells, suggesting that in RAW 264.7 cells, Raf-1 kinase is not an activating component of the LPS signaling pathway regulating MAPK activity or sIL-1Ra promoter activity. This observation was supported by results from transfection studies which demonstrated that expression of a dominant-inhibitory Raf-1 mutant in RAW 264.7 cells does not inhibit LPS-induced MAPK activity or sIL-1Ra promoter activity, indicating that LPS-induced sIL-1Ra promoter activation occurs independent of the Raf-1/MAPK signaling pathway. In additional studies, cotransfection of RAW 264.7 cells with pRA-294-luc and increasing amounts of pRSV-Raf-BXB caused a dose-dependent inhibition of LPS-induced sIL-1Ra promoter activity, indicating that the role of the Raf-1 pathway in the regulation of sIL-1Ra promoter activity by LPS is as an antagonizer. Interestingly, LPS treatment of RAW 264.7 cells, cotransfected with pRA-294-luc and pRSV-Raf-BXB, also inhibited pRSV-Raf-BXB-induced sIL-1Ra promoter activity, suggesting that inductions of sIL-1Ra promoter activity by LPS and Raf-1 actually occur by mutually antagonistic mechanisms. In support of this conclusion, sIL-1Ra promoter mapping studies indicated that LPS and Raf-1 responses localized to different regions of the sIL-1Ra promoter. Further studies demonstrated that mutual antagonism between the LPS and Raf-1 kinase pathways is not promoter specific, as the same phenomenon is observed in assays using a c-fos enhancer/thymidine kinase promoter/luciferase construct (pc-fos-TK81-luc). Additionally, mutual antagonism with regard to sIL-1Ra promoter activity also was observed between the LPS and MEK kinase pathways, indicating that mutual antagonism can occur in more than one MAPK activation pathway. PMID:9032239

  10. Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension.

    PubMed

    Kingman, Martha; Ruggiero, Rosechelle; Torres, Fernando

    2009-08-01

    Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ET(A)-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential. PMID:19601701

  11. Biological and Conformational Evaluation of Bifunctional Compounds for Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists Possessing Two Penicillamines

    PubMed Central

    Yamamoto, Takashi; Nair, Padma; Jacobsen, Neil E.; Kulkarni, Vinod; Davis, Peg; Ma, Shou-wu; Navratilova, Edita; Yamamura, Henry I.; Vanderah, Todd W.; Porreca, Frank; Lai, Josephine; Hruby, Victor J.

    2010-01-01

    Neuropathic pain states and tolerance to opioids can result from system changes in the CNS, such as up-regulation of the NK1 receptor and substance P, which have anti-opioid effects in ascending or descending pain-signaling pathways. Bifunctional compounds, possessing both the NK1 antagonist pharmacophore and the opioid agonist pharmacophore with delta-selectivity, could counteract these system changes to have significant analgesic efficacy without undesirable side effects. As a result of the introduction of cyclic and topological constraints with penicillamines, 2 (Tyr-cyclo[D-Pen-Gly-Phe-Pen]-Pro-Leu-Trp-NH-[3?,5?-(CF3)2-Bzl]) was found as the best bifunctional compound with effective NK1 antagonist and potent opioid agonist activities, and 1400-fold delta-selectivity over the mu-receptor. The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional activities as well as its significant delta-opioid selectivity. Together with the observed high metabolic stability, 2 could be considered as a valuable research tool and possibly a promising candidate for a novel analgesic drug. PMID:20617791

  12. Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects.

    PubMed

    Cleator, John H; Duvernay, Matthew T; Holinstat, Michael; Colowick, Nancy E; Hudson, Willie J; Song, Yanna; Harrell, Frank E; Hamm, Heidi E

    2014-10-01

    Although resistance to the P2Y12 antagonist clopidogrel is linked to altered drug metabolism, some studies suggest that these pharmacokinetic abnormalities only partially account for drug resistance. To circumvent pharmacokinetic complications and target P2Y12 receptor function we applied the direct P2Y12 antagonist 2-methylthio-AMP (2-methylthioadenosine 5'-monophosphate triethylammonium salt) to purified platelets ex vivo. Platelets were purified from healthy and type 2 diabetes mellitus (T2DM) patients and stimulated with thrombin or the selective protease-activated receptor agonists, protease-activated receptor 1-activating peptide (PAR1-AP), or PAR4-AP. Platelet activation as measured by ?IIb?3 activation, and P-selectin expression was monitored in 141 subjects. Our results demonstrate that, compared with healthy subjects, platelets from diabetic patients are resistant to inhibition by 2-methylthio-AMP, demonstrating P2Y12 pharmacodynamic defects among diabetic patients. Inhibition of thrombin-mediated ?IIb?3 activation by 2-methylthio-AMP was lower in diabetic platelets versus healthy platelets. Subgroup analysis revealed a racial difference in the resistance to 2-methylthio-AMP. We found no resistance in platelets from diabetic African Americans; they were inhibited by 2-methylthio-AMP equally as well as platelets from healthy African Americans. In contrast, platelets from Caucasian patients with diabetes were resistant to P2Y12 antagonism compared with healthy Caucasians. Multivariable analysis demonstrated that other variables, such as obesity, age, or gender, could not account for the differential resistance to 2-methylthio-AMP among races. These results suggest that in addition to altered drug metabolism, P2Y12 receptor function itself is altered in the Caucasian diabetic population. The racial difference in platelet function in T2DM is a novel finding, which may lead to differences in treatment as well as new targets for antiplatelet therapy. PMID:25052834

  13. The ?-opioid receptor subtype is required for the anorectic effect of an opioid receptor antagonist

    Microsoft Academic Search

    Jiaping Zhang; Andrea Frassetto; Ruey-Ruey C. Huang; Julie Z. Lao; Alexander Pasternak; Sheng-ping Wang; Joseph M. Metzger; Alison M. Strack; Tung M. Fong; Richard Z. Chen

    2006-01-01

    A diaryl ether derivative, (6-(4-{[(3-methylbutyl)amino]methyl}phenoxy)nicotinamide, was prepared and investigated for its biochemical properties at cloned opioid receptors and its pharmacological effects on animal feeding. The compound displaced [3H]DAMGO binding of human ?-opioid receptor, [3H]U-69593 of human ?-opioid receptor, and [3H]DPDPE of human ?-opioid receptor with IC50 values of 0.5±0.2 nM, 1.4±0.2 nM, and 71±15 nM, respectively. The compound also potently inhibited [3H]DAMGO binding

  14. (1R, 3S)-(?)-Trans-PAT: A novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity

    PubMed Central

    Booth, Raymond G.; Fang, Lijuan; Huang, Yingsu; Wilczynski, Andrzej; Sivendran, Sashikala

    2009-01-01

    The serotonin 5-HT2A, 5-HT2B, and 5-HT2C G protein-coupled receptors signal primarily through G?q to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT2C receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT2C agonists that do not also activate 5-HT2A or 5-HT2B receptors is challenging because transmembrane domain identity is about 75% among 5-HT2 subtypes. This paper reports 5-HT2 receptor affinity and function of (1R,3S)-(?)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), a small molecule that produces anorexia and weight-loss after peripheral administration to mice. (?)-Trans-PAT is a stereoselective full-efficacy agonist at human 5-HT2C receptors, plus, it is a 5-HT2A/5-HT2B inverse agonist and competitive antagonist. The Ki of (?)-trans-PAT at 5-HT2A, 5-HT2B, and 5-HT2C receptors is 410, 1200, and 37 nM, respectively. Functional studies measured activation of PLC/[3H]-IP formation in clonal cells expressing human 5-HT2 receptors. At 5-HT2C receptors, (?)-trans-PAT is an agonist (EC50 = 20 nM) comparable to serotonin in potency and efficacy. At 5-HT2A and 5-HT2B receptors, (?)-trans-PAT is an inverse agonist (IC50 = 490 and 1,000 nM, respectively) and competitive antagonist (KB = 460 and 1400 nM, respectively) of serotonin. Experimental results are interpreted in light of molecular modeling studies indicating the (?)-trans-PAT protonated amine can form an ionic bond with D3.32 of 5-HT2A and 5-HT2C receptors, but, not with 5-HT2B receptors. In addition to probing 5-HT2 receptor structure and function, (?)-trans-PAT is a novel lead regarding 5-HT2C agonist/5-HT2A inverse agonist drug development for obesity and neuropsychiatric disorders. PMID:19397907

  15. 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, E-mail: molinajm@ugr.es [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain); Amaya, Esperanza [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain); Grimaldi, Marina [INSERM, U896, Montpellier F-34298 (France); Université de Montpellier I, Montpellier F-34298 (France); Sáenz, José-María; Real, Macarena; Fernández, Mariana F. [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain); Balaguer, Patrick [INSERM, U896, Montpellier F-34298 (France); Université de Montpellier I, Montpellier F-34298 (France); Olea, Nicolás [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain)

    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 (hER?), 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 (hER? and hER?), 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 hER? agonist. Unlike BPF and BPA, BPS was more active in the hER? versus hER? 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 hER?, hER?, 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.

  16. Effects of tachykinin NK1 receptor antagonists on vagal hyperreactivity and neuronal M2 muscarinic receptor function in antigen challenged guinea-pigs

    PubMed Central

    Costello, Richard W; Fryer, Allison D; Belmonte, Kristen E; Jacoby, David B

    1998-01-01

    The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs.In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1–100??g?kg?1, i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24?h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4?mg?kg?1, i.p.), SR140333 (1?mg?kg?1, s.c.) or CP96345 (15?mg?kg?1, i.p.) before antigen challenge, prevented M2 receptor dysfunction.Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5??mol?kg?1, i.p.), before antigen challenge, prevented M2 receptor dysfunction.Electrical stimulation of the vagus nerves caused a frequency-dependent (2–15?Hz, 10?V, 0.2?ms for 5?s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase.Histamine (1–20?nmol?kg?1, i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity.Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994.These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves. PMID:9641542

  17. The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats.

    PubMed

    Hirsch, Silke; Corradini, Laura; Just, Stefan; Arndt, Kirsten; Doods, Henri

    2013-05-01

    Calcitonin gene-related peptide (CGRP) is known to play a major role in the pathogenesis of pain syndromes, in particular migraine pain. Here we focus on its implication in a rat pain model of inflammation, induced by injection of complete Freund adjuvant (CFA). The nonpeptide CGRP receptor antagonist BIBN4096BS reduces migraine pain and trigeminal neuronal activity. Here we demonstrate that the compound reduces inflammatory pain and spinal neuronal activity. Behavioural experiments reveal a reversal of the CFA-induced mechanical hypersensitivity and monoiodoacetate (MIA)-induced weight-bearing deficit in rats after systemic drug administration. To further investigate the mechanism of action of the CGRP antagonist in inflammatory pain, in vivo electrophysiological studies were performed in CFA-injected rats. Recordings from wide dynamic range neurons in deep dorsal horn layers of the lumbar spinal cord confirmed a reduction of neuronal activity after systemic drug application. The same amount of reduction occurred after topical administration onto the paw, with resulting systemic plasma concentrations in the low nanomolar range. However, spinal administration of BIBN4096BS did not modify the neuronal activity in the CFA model. Peripheral blockade of CGRP receptors by BIBN4096BS significantly alleviates inflammatory pain. PMID:23473785

  18. Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists.

    PubMed

    Katritch, Vsevolod; Jaakola, Veli-Pekka; Lane, J Robert; Lin, Judy; Ijzerman, Adriaan P; Yeager, Mark; Kufareva, Irina; Stevens, Raymond C; Abagyan, Ruben

    2010-02-25

    The recent progress in crystallography of G-protein coupled receptors opens an unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screening (VLS) of more than 4 million commercially available "drug-like" and ''lead-like'' compounds against the A(2A)AR 2.6 A resolution crystal structure. Out of 56 high ranking compounds tested in A(2A)AR binding assays, 23 showed affinities under 10 microM, 11 of those had sub-microM affinities and two compounds had affinities under 60 nM. The identified hits represent at least 9 different chemical scaffolds and are characterized by very high ligand efficiency (0.3-0.5 kcal/mol per heavy atom). Significant A(2A)AR antagonist activities were confirmed for 10 out of 13 ligands tested in functional assays. High success rate, novelty, and diversity of the chemical scaffolds and strong ligand efficiency of the A(2A)AR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery. PMID:20095623

  19. In vivo pharmacological characterization of the non-peptide endothelin receptor antagonist SB 209670.

    PubMed Central

    Douglas, S A; Edwards, R M; Elliott, J D; Ohlstein, E H

    1995-01-01

    1. The aim of the present study was to assess the ability of SB 209670, a high affinity non-peptide endothelin receptor antagonist (0.4 and 18 nM Kis at human cloned ETA and ETB receptors, respectively), to inhibit the haemodynamic actions of endothelin-1 in vivo. 2. Systemic administration of (+/-)-SB 209670, given either as a bolus i.v. injection or as a continuous i.v. infusion, did not alter basal haemodynamic parameters in the anaesthetized rat. 3. Infusion of (+/-)-SB 209670 (10 micrograms kg-1 min-1) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin-1: 100 micrograms kg-1 min-1 was required to inhibit significantly the biphasic haemodynamic actions of endothelin-1. The haemodynamic actions of angiotensin II and calcitonin gene-related peptide were unaltered by 100 micrograms kg-1 min-1 (+/-)-SB 209670. 4. Bolus i.v. administration of (+/-)-SB 209670 (1 mg kg-1) selectively inhibited the depressor and carotid vasodilator actions of endothelin-1: 10 mg kg-1 (+/-)-SB 209670 was required to inhibit the secondary vasoconstrictor actions of endothelin-1. 5. (+/-)-SB 209670 (10 mg kg-1) was also effective at antagonizing the pressor actions of endothelin-1 in the conscious rat for up to 3 h after intraduodenal administration thereby demonstrating that the antagonist was bioavailable upon enteric administration. This dose of (+/-)-SB 209670 did not alter basal haemodynamic parameters in the conscious rat.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7881741

  20. Churg Strauss syndrome during treatment of bronchial asthma with a leucotriene receptor antagonist presenting with polyneuropathy.

    PubMed

    Oberndorfer, S; Beate, U; Sabine, U; Peter, H; Heinz, L; Barabra, H; Wolfgang, G

    2004-04-01

    Bronchial asthma can be associated with Churg Strauss syndrome (CSS). A peripheral neuropathy may be the initial manifestation of CSS. There is also some evidence that leucotriene receptor antagonists (LTAs) may trigger CSS in asthmatic patients, especially when steroids are tapered previously. However, the pathogenesis is unclear and the association between CSS and LTAs remains a matter of controversy. The aim of this report is to clarify this issue. A 79-year-old male patient with bronchial asthma for twenty years was admitted due to progressing gait disorder developing within the last two weeks. Asthma had been treated with a leucotriene receptor antagonist (Montelukast) for four years, as well as low doses of inhaled steroids and beta-2-agonists. On admission, neurological examination revealed a mild ataxia on both upper limbs and multifocal sensory disturbances without motor deficits. Nerve conduction velocity studies demonstrated normal results for the upper limbs and an axonal sensorimotor neuropathy of the lower limbs. Electromyography exhibited no spontaneous activity in the right tibialis anterior and rectus femoris muscle. Nerve-muscle biopsy revealed an eosinophilic vasculitis in both nerve and muscle. Laboratory examination showed leucocytosis and marked eosinophilia. A diagnosis of CSS was made. This case demonstrates a severe neuropathy in an asthmatic patient, during long lasting treatment with a LTA and continuous low doses of inhaled steroid, as the initial clinical feature of CSS. PMID:15088164

  1. Receptor-mediated binding and uptake of GnRH agonist and antagonist by pituitary cells

    SciTech Connect

    Jennes, L.; Stumpf, W.E.; Conn, P.M.

    1984-01-01

    The intracellular pathway of an enzyme resistant GnRH agonist (D- Lys6 -GnRH) conjugated to ferritin or to colloidal gold was followed in cultured pituitary cells. After an initial uniform distribution over the cell surface of gonadotropes, the electrondense marker was internalized, either individually or in small groups. After longer incubation times, the marker appeared in the lysosomal compartment and the Golgi apparatus, where it could be found in the vesicular as well as cisternal portion. In addition, the receptor-mediated endocytosis of the GnRH antagonist D-p-Glu1-D-Phe2-D-Trp3-D- Lys6 -GnRH was studied by light and electron microscopic autoradiography after 30 and 60 min of incubation to ensure uptake. At both time points, in in vitro as well as in vivo studies, silver grains were localized over cytoplasmic organelles of castration cells, including dilated endoplasmic reticulum, lysosomes, and clear vesicles. No consistent association with cell nuclei, mitochondria, or secretory vesicles could be observed. The results suggest that both agonist and antagonist are binding selectively to the plasma membrane of gonadotropes and subsequently are taken up via receptor-mediated endocytosis for degradation or possible action on synthetic processes.

  2. Aldosterone receptor antagonists in cardiovascular disease: a review of the recent literature and insight into potential future indications.

    PubMed

    Markowitz, Mindy; Messineo, Frank; Coplan, Neil L

    2012-10-01

    Randomized controlled trials demonstrate the efficacy of aldosterone receptor antagonists (spironolactone and eplerenone) as a useful pharmacologic intervention specifically in patients with New York Heart Association (NYHA) class III and IV heart failure, in patients with an ejection fraction <40% after myocardial infarction, and most recently in patients with mildly symptomatic heart failure. However, aldosterone receptor antagonists may be beneficial in a broader patient population. Aldosterone receptor antagonists can potentially serve as an antiarrhythmic pharmacologic agent for atrial and ventricular arrhythmias, an anti-ischemic medication in coronary artery disease through prevention of myocardial fibrosis and vascular damage, and as an agent in people with asymptomatic and mild heart failure (NYHA classes I and II) and diastolic heart failure. However, many clinicians remain reluctant to prescribe this highly efficacious pharmacologic therapy for a variety of reasons, including concerns about polypharmacy and hyperkalemia. Recent observational analysis demonstrates that less than one-third of eligible patients hospitalized with heart failure actually received aldosterone antagonist therapy. This article will review the current and potential future uses of aldosterone receptor antagonists across the entire spectrum of cardiovascular disease. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID:22778046

  3. Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1.

    PubMed

    Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ågren, Hans; Tu, Yaoquan

    2015-01-01

    The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R. PMID:25628267

  4. Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1

    PubMed Central

    Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ågren, Hans; Tu, Yaoquan

    2015-01-01

    The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr6.63 forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr6.63 to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr3566.63 allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R. PMID:25628267

  5. A Meta-Analysis and Indirect Comparison of Endothelin A Receptor Antagonist for Castration-Resistant Prostate Cancer

    PubMed Central

    Zhang, Li-xiu; Song, Rui-xia; He, Zhen-hua; Wang, Zhi-ping

    2015-01-01

    Background Endothelin A (ET-A) receptor antagonists including zibotentan and atrasentan, have been suggested as a treatment for castration-resistant prostate cancer (CRPC). Our aim was to conduct a meta-analysis and indirect comparison to assess the efficacy and safety of ET-A receptor antagonists for treatment of CRPC. Methods We systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science from inception to November 2014 to identify randomized controlled trials (RCTs) which assessed ET-A receptor antagonists for treatment of CRPC. Meta-analysis was conducted by STATA version 12.0 software. Results Eight RCTs were identified, involving 6,065 patients. The results of direct comparison showed that compared with placebo, there was no statistically significant difference in the improvement of progression-free survival (PFS), overall survival (OS), time to disease progression (TTP), and total adverse events (AEs) with ET-A receptor antagonist treatment for CRPC. The results of ET-A receptor antagonists plus docetaxel versus docetaxel alone were similar. The indirect comparisons showed that there were no significant differences between zibotentan plus docetaxel versus atrasentan plus docetaxel when compared with docetaxel alone or zibotentan versus atrasenta compared with placebo in the improvement of PFS, OS, TTP, and total adverse events. Conclusions There were no significant benefits for ET-A receptor antagonists with or without docetaxel in the improvement of PFS, OS, TTP, and overall AEs. And there were no significant differences between zibotentan and atrasentan. Single-agent docetaxel should remain as one of the standard treatments. PMID:26192308

  6. Functionalized congeners of tyrosine-based P2X(7) receptor antagonists: probing multiple sites for linking and dimerization.

    PubMed

    Chen, Wangzhong; Ravi, R Gnana; Kertesy, Sylvia B; Dubyak, George R; Jacobson, Kenneth A

    2002-01-01

    Chemically funtionalized analogues of antagonists of the P2X(7) receptor, an ATP-gated cation channel, were synthesized as tools for biophysical studies of the receptor. These functionalized congeners were intended for use in chemical conjugation with retention of biological potency. The antagonists were L-tyrosine derivatives, related to [N-benzyloxycarbonyl-O-(4-arylsulfonyl)-L-tyrosyl]benzoylpiperazine (such as MRS2409, 2). The analogues were demonstrated to be antagonists in an assay of human P2X(7) receptor function, consisting of inhibition of ATP-induced K(+) efflux in HEK293 cells expressing the recombinant receptor. The analogues were of the general structure R(1)-Tyr(OR(2))-piperazinyl-R(3), in which three positions (R(1)-R(3)) were systematically varied in structure through introduction of chemically reactive groups. Each of the three positions was designed to incorporate a 3- or 4-nitrophenyl group. The nitro groups were reduced using NaBH(4)-copper(II) acetylacetonate to amines, which were either converted to the isothiocyanate groups, as potential affinity labels for the receptor, or acylated, as models for conjugation. An alternate route to N(alpha)-3-aminobenzyloxycarbonyl functionalization was devised. The various positions of functionalization were compared for effects on biological potency, and the R(2) and R(3) positions were found to be most amenable to derivatization with retention of high potency. Four dimeric permutations of the antagonists were synthesized by coupling each of the isothiocyanate derivatives to either the precursor amine or to other amine congeners. Only dimers linked at the R(2)-position were potent antagonists. In concentration-response studies, two derivatives, a 3-nitrobenzyloxycarbonyl derivative 18 and a 4-nitrotoluenesulfonate 26b, displayed IC(50) values of roughly 100 nM as antagonists of P2X(7) receptor-mediated K(+) flux. PMID:12236792

  7. Mapping peptide-binding domains of the human V1a vasopressin receptor with a photoactivatable linear peptide antagonist.

    PubMed

    Phalipou, S; Cotte, N; Carnazzi, E; Seyer, R; Mahe, E; Jard, S; Barberis, C; Mouillac, B

    1997-10-17

    The study of antagonist-binding domains of the human V1a vasopressin receptor was performed using a radioiodinated photoreactive peptide antagonist. This ligand displayed a high affinity for the receptor expressed in Chinese hamster ovary cell membranes, and specifically labeled two protein bands with apparent molecular mass at 85-90 and 46 kDa. Our results clearly show that the V1a receptor is degraded during incubation with the ligand and that the 46-kDa species is probably the result of the 85-90-kDa species proteolytic cleavage. Truncation of the receptor was then confirmed by deglycosylation with N-glycosidase F. A monoclonal antibody directed against a c-Myc epitope added at the receptor NH2 terminus allowed immunoprecipitation of the 85-90-kDa photolabeled species. The 46-kDa photolabeled protein never immunoprecipitated, indicating that the truncated form of the receptor lacks the NH2 terminus region. To localize photolabeled domains of the receptor, the 46-kDa protein was cleaved with V8 and/or Lys-C endoproteinases. The identity of the smallest photolabeled fragment, observed at approximately 6 kDa, was then confirmed by mutation of the potential V8 cleavage sites. Our results indicate that covalent labeling of the vasopressin V1a receptor with the photoreactive antagonist occurs in a region including transmembrane domain VII (residues Asn327-Lys370). PMID:9334232

  8. Effects of adrenalectomy and glucocorticoid receptor antagonist, RU38486, on pituitary growth hormone-releasing hormone receptor gene expression in rats

    Microsoft Academic Search

    Tomoyo Ohyama; Makoto Sato; Hidemi Ohye; Koji Murao; Michio Niimi; Jiro Takahara

    1998-01-01

    We examined the effects of adrenalectomy and a glucocorticoid receptor antagonist, RU38486, on pituitary GH-releasing hormone (GRH) receptor gene expression in rats. GRH receptor mRNA levels were significantly decreased in adrenalectomized rats and replacement of dexamethasone reversed the decrease to normal. GH secretion was inhibited by adrenalectomy, whereas dexamethasone replacement failed to restore the impaired GH secretion. A high dose

  9. LY215840, a potent 5-hydroxytryptamine (5-HT)2 receptor antagonist, blocks vascular and platelet 5-HT2 receptors and delays occlusion in a rabbit model of thrombosis.

    PubMed

    Cohen, M L; Robertson, D W; Bloomquist, W E; Wilson, H C

    1992-04-01

    Certain ergolines are potent and selective 5-hydroxytryptamine (5-HT)2 receptor antagonists. Previous studies with two ergoline esters, LY53857 and sergolexole, documented their potency as 5-HT2 receptor antagonists and their metabolism in rats to a less active metabolite, 1-isopropyl dihydrolysergic acid. LY215840, an ergoline amide, has been identified as a potent 5-HT2 receptor antagonist that is not hydrolyzed to 1-isopropyl dihydrolysergic acid. In the rat jugular vein, LY215840 (3 x 109-10) to 10(-8) M) blocked 5-HT2 receptors mediating contraction to 5-HT in vitro. After i.v. and p.o. administration to rats, LY215840 was a potent 5-HT2 receptor antagonist, documented by its ability to block the pressor response to 5-HT administered i.v. Furthermore, after i.v. and p.o. administration of LY215840, blockade of vascular 5-HT2 receptors persisted in excess of 2 and 6 hr, respectively. LY215840 also blocked vascular 5-HT2 receptors in doses that did not affect alpha-1, beta-1 receptors or angiotensin II pressor responses, documenting the selectivity of LY215840 as an inhibitor of 5-HT2 and not other vascular receptors that modulate vasoconstriction. In addition to inhibiting vascular 5-HT2 receptors, LY215840 also inhibited 5-HT-amplified, ADP-induced aggregation (another 5-HT2 receptor-mediated response) in both rabbit and human platelets. Because of its ability to block both platelet and vascular 5-HT2 receptors, we studied the effectiveness of LY215840 in the rabbit carotid artery model of vascular occlusion. Low i.v. doses of LY215840 markedly prolonged time to vascular occlusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1560366

  10. Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist

    Microsoft Academic Search

    Yuji Shishido; Fumitaka Ito; Hiromasa Morita; Masaya Ikunaka

    2007-01-01

    A novel neurokinin-1 receptor antagonist, (±)-(1R?,3S?,4S?,5S?)-4-[(N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane (1), was synthesized stereoselectively using Padwa’s intramolecular 1,3-dipolar cycloaddition methodology as the key step. Compound (±)-1 showed high affinity for the NK-1 receptors in human IM-9 cells with an IC50 value of 0.22nM. This new structural scaffold demonstrated significant in vivo antagonistic activity in the guinea pig ureter capsaicin-induced plasma extravasation model with an

  11. Effects of Urotensin II and Its Specific Receptor Antagonist Urantide on Rat Vascular Smooth Muscle Cells

    PubMed Central

    Zhao, Juan; Zhang, Shu-Feng; Shi, Yan; Ren, Li-Qun

    2013-01-01

    We investigated the effects of urantide, a receptor antagonist of urotensin II (U-II), on the expression of U-II and its receptor GPR14 in rat vascular smooth muscle cells. Vascular smooth muscle cells from rat thoracic aorta were cultured by explant method. Subjects in this experiment were divided into eight groups: normal control group (group C), U-II group (group M), positive control group (Flu group) and urantide-treated groups (10-10, 10-9, 10-8, 10-7 and 10-6 mol/L). Cultured vascular smooth muscle cells in vitro were studied by immunocytochemistry, biochemistry, and flow cytometry. U-II (10-8 mol/L) promoted the proliferation of vascular smooth muscle cells at each time point, influenced cell cycle, increased proliferation index and S-phase cell fraction, and dramatically promoted the expression of U-II and GPR14. In the concentration range from 10-10 to 10-6 mol/L, urantide dramatically inhibited the proliferation of vascular smooth muscle cells and the protein expression of U-II and GPR14, especially at a concentration of 10-6 mol/L. U-II, binding with its receptor GPR14, promotes vascular smooth muscle cells proliferation and migration, which can be inhibited by urantide. This study provides an evidence for understanding the effects of U-II and its receptor GPR14 on vascular smooth muscle cells. PMID:23725502

  12. Daphnia magna responses to a vertebrate estrogen receptor agonist and an antagonist: a multigenerational study.

    PubMed

    Clubbs, Rebekah L; Brooks, Bryan W

    2007-07-01

    Whereas ecological risk assessments rely on standardized aquatic toxicity tests to assess ecological hazards, these techniques have limited utility for endocrine-active compounds, including select pharmaceuticals. Due to structural similarity between of vertebrate estrogens and ecdysone, previous studies suggest that endocrine-active pharmaceuticals may interfere with invertebrate endocrine systems, while other investigations do not support these suggestions. We assessed effects of the pharmaceuticals 17alpha-ethinylestradiol and faslodex, model therapeutics designed to interact with vertebrate estrogen receptors, on endocrine biomarkers and transgenerational life-history parameters of a model invertebrate, Daphnia magna. Identical studies were performed with 20-hydroxyecdysone and testosterone, which served as positive controls for ecdysteroid receptor agonism and antagonism, respectively. Results from this study at biochemical, individual and population levels suggest that a mammalian estrogen receptor agonist and antagonist did not act through the ecdysone receptor in D. magna. Acute-to-chronic ratios based on various chronic responses ranged from 2.59 to 5.18 for 17alpha-ethinylestradiol and 1.29-12.9 for faslodex. Toxicity exerted by these therapeutics on D. magna likely resulted from non-endocrine-mediated responses. Mechanism-specific biomarkers, multigenerational designs and population growth models may be useful to assess organismal and population level responses to low-level exposures, which may serve to reduce uncertainty in future hazard assessments of invertebrate responses to endocrine-active pharmaceuticals in the environment. PMID:17368538

  13. A Novel Series of Piperidin-4-yl-1,3-Dihydroindol-2-ones as Agonist and Antagonist Ligands at the Nociceptin Receptor

    PubMed Central

    Zaveri, Nurulain T.; Jiang, Faming; Olsen, Cris M.; Deschamps, Jeffrey R.; Parrish, Damon; Polgar, Willma; Toll, Lawrence

    2013-01-01

    A series of N-(4-piperidinyl)-2-indolinones were discovered as a new structural class of nociceptin receptor (NOP) ligands. Unlike other previously reported classes of NOP receptor ligands, modifications of the piperidine N substituents afforded both potent agonists and antagonists, with modest selectivities over other opioid receptors. The SAR revealed in this new series will provide important insights for the development of pharmacophores for agonist and antagonist actions at the NOP receptor. PMID:15163178

  14. The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors, in vitro.

    PubMed

    Wong, E H; Clark, R; Leung, E; Loury, D; Bonhaus, D W; Jakeman, L; Parnes, H; Whiting, R L; Eglen, R M

    1995-02-01

    1. A series of isoquinolines have been identified as 5-HT3 receptor antagonists. One of these, RS 25259-197 [(3aS)-2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro- 1- oxo-1H-benzo[de]isoquinoline-hydrochloride], has two chiral centres. The remaining three enantiomers are denoted as RS 25259-198 (R,R), RS 25233-197 (S,R) and RS 25233-198 (R,S). 2. At 5-HT3 receptors mediating contraction of guinea-pig isolated ileum, RS 25259-197 antagonized contractile responses to 5-HT in an unsurmountable fashion and the apparent affinity (pKB), estimated at 10 nM, was 8.8 +/- 0.2. In this tissue, the -log KB values for the other three enantiomers were 6.7 +/- 0.3 (R,R), 6.7 +/- 0.1 (S,R) and 7.4 +/- 0.1 (R,S), respectively. The apparent affinities of RS 25259-197 and RS 25259-198, RS 25233-197 and RS 25233-198 at 5-HT3 receptors in membranes from NG-108-15 cells were evaluated by a [3H]-quipazine binding assay. The -log Ki values were 10.5 +/- 0.2, 8.4 +/- 0.1, 8.6 +/- 0.1 and 9.5 +/- 0.1, respectively, with Hill coefficients not significantly different from unity. Thus, at these 5-HT3 receptors, the rank order of apparent affinities was (S,S) > (R,S) > (S,R) = (R,R). 3. RS 25259-197 displaced the binding of the selective 5-HT3 receptor ligand, [3H]-RS 42358-197, in membranes from NG-108-15 cells, rat cerebral cortex, rabbit ileal myenteric plexus and guinea-pig ileal myenteric plexus, with affinity (pKi) values of 10.1 +/- 0.1, 10.2 +/- 0.1, 10.1 +/- 0.1 and 8.3 +/- 0.2, respectively. In contrast, it exhibited low affinity (pKi <6.0) at 28 other receptors in binding assays, including adrenoceptors (alpha1A, alpha 1B, alpha2A, alpha 2B ,beta1, beta2), muscarinic (M1-M4), dopamine (D1, D2), opioid and other 5-HT(5-HTlA, 5-HTlD, 5-HT2C, 5-HT4) receptors.4. RS 25259-197 was tritium labelled (specific activity: 70 Ci mmol-1) and evaluated in pharmacological studies. Saturation studies with [3H]-RS 25259-197 in membranes from NG-108-15 and cloned homomeric a subunits of the 5-HT3 receptor from N1E-1 15 cells expressed in human kidney 293E1 cells,revealed an equilibrium dissociation constant (Kd) of 0.05 +/- 0.02 and 0.07 +/- 0.01 nM, and Bmax of610 +/- 60 and 1068 +/- 88 fmol mg-1, respectively. Competition studies in NG-108-15 cells indicated a pharmacological specificity entirely consistent with labelling a 5-HT3 receptor, i.e. RS 25259-197> granisetron> (S)-zacopride> tropisetron> (R)-zacopride> ondansetron> MDL 72222.5. In contrast to the majority of radioligands available to label 5-HT3 receptors, [3H]-RS 25259-197 labelled a high affinity site in hippocampus from human post-mortem tissue with an equilibrium dissociation constant (Kd) of 0.15 +/- 0.07 nM and density (BmaX) of 6.8 +/- 2.4 fmol mg-1 protein. Competition studies in this tissue indicated a pharmacological specificity consistent with labelling of a 5-HT3receptor.6. Quantitative autoradiographic studies in rat brain indicated a differential distribution of 5-HT3receptor sites by [3H]-RS 25259-197. High densities of sites were seen in nuclear tractus solitaris and area postrema, a medium density in spinal trigeminal tract, ventral dentate gyrus and basal medial amygdala,and a low density of sites in hippocampal CAl, parietal cortex, medium raphe and cerebellum.7 In conclusion, the functional, binding and distribution studies undertaken with the radiolabelled and non-radiolabelled RS 25259-197 (S,S enantiomer) established the profile of a highly potent and selective5-HT3 receptor antagonist. PMID:7773546

  15. The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold

    PubMed Central

    2013-01-01

    Background Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism of action. Results Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. Conclusion The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses. PMID:23981345

  16. Comparison of the structure-activity relationships of melatonin receptor agonists and antagonists: lengthening the N-acyl side-chain has differing effects on potency on Xenopus melanophores.

    PubMed

    Teh, M T; Sugden, D

    1998-11-01

    The potency and affinity of two series of melatonin receptor ligands were examined using the pigment aggregation response in a clonal line of Xenopus laevis melanophores and radioligand binding assays on native receptors in chicken brain, recombinant human mt1 and MT2 and Xenopus laevis mel1c receptor subtypes. One series was based on melatonin and had a methoxy group at the 5-position of the indole ring, while the other was based on luzindole and lacked this substituent but did have a 2-benzyl moiety; the N-acyl group of each series of analogues was varied from one to five carbon atoms. All analogues in the melatonin series were full agonists in melanophores (pEC50 7.76-10.24), while all compounds in the luzindole series were competitive melatonin antagonists (pA2 5.47-6.60). With the agonist series, increasing the N-acyl side-chain from one to three carbon atoms was well tolerated in both the functional and binding assays, but further lengthening of the side-chain progressively and dramatically reduced potency and affinity. In contrast, for the antagonist series neither potency nor binding affinity changed substantially with the length of the N-acyl chain, except at the recombinant MT2 subtype where two of the analogues had a lower affinity. In binding assays, three of the five antagonists were MT2-selective; the most selective analogue (N-pentanoyl 2-benzyltryptamine, MT2 pKi 8.03) having 89- and 229-fold higher affinity than at mt1 or mel1c receptor subtypes. The different structure-activity relationships of these receptor agonists and antagonists is discussed with regard to the possible binding sites of agonists and antagonists within the receptor protein. PMID:9840420

  17. The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657

    PubMed Central

    Asano, Masayuki; Inamura, Noriaki; Hatori, Chie; Sawai, Hiroe; Fujiwara, Tatsujiro; Katayama, Akira; Kayakiri, Hiroshi; Satoh, Shigeki; Abe, Yoshito; Inoue, Takayuki; Sawada, Yuki; Nakahara, Kunio; Oku, Teruo; Okuhara, Masakuni

    1997-01-01

    An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3?-?pyridyl)?-?N?-?[N?-?[2?-?4?-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide) has been identified.This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6×10?10?M and in rat uterus with an IC50 of 1.5×10?9?M. It did not inhibit different specific radio-ligand binding to other receptor sites.In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9×10?9?M and a Ki of 3.6×10?10?M, but did not reduce [3H]-des-Arg10-kallidin binding to B1 receptors.In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9×10?9?M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10?6?M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10?9?M and 3.2×10?9?M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10?8?M. Analysis of the data yield a pA2 of 9.2±0.2 (n=5) and a slope of 1.5±0.2 (n=5).In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075?mg?kg?1, but did not inhibit histamine-induced bronchoconstriction even at 1?mg?kg?1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8?mg?kg?1 2?h after the carrageenin injection in rats.These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist. PMID:9051299

  18. Bone Morphogenetic Protein Type I Receptor Antagonists Decrease Growth and Induce Cell Death of Lung Cancer Cell Lines

    PubMed Central

    Langenfeld, Elaine; Hong, Charles C.; Lanke, Gandhi; Langenfeld, John

    2013-01-01

    Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade. PMID:23593444

  19. Tritium-labelled isovaleryl-RYYRIK-NH2 as potential antagonist probe for ORL1 nociceptin receptor.

    PubMed

    Inamine, Shogo; Nishimura, Hirokazu; Li, Jinglan; Isozaki, Kaname; Matsushima, Ayami; Costa, Tommaso; Shimohigashi, Yasuyuki

    2014-11-01

    IsoVa-RYYRIK-NH2 is a highly specific antagonist ligand of the opioid receptor-like 1 (ORL1) receptor, an endogenous ligand of which is 17-mer peptide nociceptin. ORL1 antagonists have potential for clinical use as analgesic and antineuropathic drugs, and thus information on the receptor-binding characteristics of antagonists is very important for rational drug design. In the present study, we prepared tritium-labelled isova-RYYRIK-NH2 from its precursor with the 3-methylcrotonyl (CH3)2CCHCO group by a catalytic reduction using tritium gas. The resulting [(3)H]isoVa-RYYRIK-NH2 was evaluated in a saturation binding assay using the COS-7 cell membrane preparations of transiently expressed ORL1. It exhibited more than 90% specific binding with a dissociation constant of 1.21±0.03nM. From the mutual heterologous binding assays using [(3)H]isoVa-RYYRIK-NH2 and [(3)H]nociceptin, isoVa-RYYRIK-NH2 and nociceptin were found to share the receptor-binding site, but each also had a separate specific binding site of its own. They differentiated the two different binding states or conformations of ORL1, which might represent the agonist-active and antagonist-inactive conformations of ORL1. [(3)H]isoVa-RYYRIK-NH2 is thus a key tracer to uncover the amino acid residues important for receptor inactivation. PMID:25284251

  20. Effects of mu and kappa opioid receptor agonists and antagonists on contraction of isolated colon strips of rats with cathartic colon

    Microsoft Academic Search

    Bao-Hua Liu; Ping Mo; Sheng-Ben Zhang

    2004-01-01

    AIM: To study the effects of mu and kappa opioid receptor agonists and antagonists on the isolated colon strips of rats with cathartic colon. METHODS: Cathartic colon model was established by feeding rats with contact laxatives, and effects of mu and kappa opioid receptor agonists and antagonists on electricity- stimulated contraction of isolated colon strips of rats with cathartic colon

  1. Influence of H 1 -and H 2 -receptor antagonists on the circulatory system and on the endogenous plasma histamine concentrations in dogs

    Microsoft Academic Search

    M. Thermann; A. Schmal; F. Schingale; P. Dormann; H. Hamelmann

    1977-01-01

    The effects of the H1-receptor antagonist dimethpyrindene and the H2-receptor antagonist burimamide on circulatory and respiratory parameters and on plasma histamine levels were tested in 21 mongrel dogs. Both drugs released histamine. The incidence for this effect was 10\\/11 in the case of dimethpyrindene and 5\\/10 in the case of burimamide.

  2. Effects of histamine H1 receptor antagonists on action potentials in guinea-pig isolated papillary muscles.

    PubMed

    Ki, I; Inui, A; Ito, T

    1996-01-01

    The effects of histamine H1 receptor antagonists (H1 antagonists) on action potentials in guinea-pig isolated papillary muscles were examined using a microelectrode technique. Terfenadine (0.03 microM) prolonged the action potential duration at 90% repolarization, without affecting the resting membrane potentials, the action potential amplitude or the maximal upstroke velocity, although its metabolite, terfenadine carboxylate, did not affect any action potential parameters. Astemizole, (+)-chlorpheniramine, and clemastine prolonged the action potential duration at 90% repolarization at 0.03, I and 10 microM, respectively. The action potential duration-prolonging effects of terfenadine and astemizole correspond to the reverse use-dependence phenomenon. However, ebastine and its metabolite, carebastine, did not affect the action potential parameters at 3 microM. Mequitazine, diphenhydramine, epinastine, ketotifen and oxatomide were also without effect at 10 microM. These H1 antagonists suppressed the histamine-induced contractions in guinea-pig isolated ileum longitudinal muscles. However, the potency order was inconsistent with that for prolonging the action potential duration. Terfenadine or astemizole prolonged the action potential duration at concentrations lower than each IC50 value for H1 receptor antagonism. Cimetidine, a H2 receptor antagonist, and thioperamide, a H3 receptor antagonist, had little effect on the action potentials. These results suggest that, in guinea-pig isolated papillary muscles, blockade of histamine receptors does not cause prolongation of the action potential duration, leading to prolongation of electrocardiographic QT intervals, and that H1 antagonists may be classified into three groups: (1) drugs causing prolongation of the action potential duration at concentrations producing H1 antagonism and (2) at concentrations higher than those producing H1 antagonism, and. PMID:8896711

  3. High-resolution crystal structure of human Protease-Activated Receptor 1 bound to the antagonist vorapaxar

    PubMed Central

    Zhang, Cheng; Srinivasan, Yoga; Arlow, Daniel H.; Fung, Juan Jose; Palmer, Daniel; Zheng, Yaowu; Green, Hillary F.; Pandey, Anjali; Dror, Ron O.; Shaw, David E.; Weis, William I.; Coughlin, Shaun R.; Kobilka, Brian K.

    2012-01-01

    Protease-Activated Receptor-1 (PAR1) is the prototypical member of a family of G protein-coupled receptors that mediate cellular responses to thrombin and related proteases. Thrombin irreversibly activates PAR1 by cleaving the N-terminal exodomain of the receptor, which exposes a tethered peptide ligand that binds the receptor’s heptahelical bundle to effect G protein-activation. Here we report a 2.2Å resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by PAR1’s tethered ligand. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated GPCRs, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent. PARs are important targets for drug development. The structure reported here will aid development of improved PAR1 antagonists and discovery of antagonists to other members of this receptor family. PMID:23222541

  4. P7, a novel antagonist of corticotropin releasing factor receptor type 1 (CRFR1) screened from phage display library.

    PubMed

    Yu, Jinmei; Zhuo, Rengong; Peng, Peng; Liu, Xiaoyan; Yan, Haitao; Zhang, Shuzhuo; Zheng, Jianquan; Wei, Xiaoli; Ma, Xiaoyun

    2015-07-31

    The corticotropin releasing factor (CRF) plays a central role in regulating the activities of hypothalamic-pituitary-adrenal (HPA) axis in the presence of a variety of stressful stimuli via binding to its type 1 receptors (CRFR1). Despite that many peptidic or non-peptidic antagonists of CRFR1 have been developed to serve as therapeutic tools to CRF-related pathologies, none of them have been utilized clinically. Targeting the extracellular domain 1 (EC1) of CRFR1, the CRF-binding site, represents a new strategy to inhibit the function of the receptor. However, no such agents have been identified up to now. Herein, by using an 87-amino acid fragment corresponding to the EC1 region as the bait, we screened the binding polypeptides from a phage display (Ph.D.-12) peptide library. After 3-round biopanning, positive clones were selected and the polypeptides carried by them were identified. 5 polypeptides were found to bind with the target specifically. Among them, the P7 exhibited the highest affinity. By evaluating the cAMP accumulation in the CRFR1 or CRFR2-expressing HEK293 cells, we demonstrated that P7 blocking the function of CRFR1, but not CRFR2. In addition, we also found that P7 and CRF act on CRFR1 competitively. Taken together, we reveal that P7, a novel polypeptide identified from phage display library, inhibits the function of CRFR1 effectively and specifically by binding at its EC1 domain. The new polypeptide might provide a promising agent for diagnostic or therapeutic utilities in CRF-related disorders. PMID:25998380

  5. Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor

    PubMed Central

    Tognolini, Massimiliano; Incerti, Matteo; Mohamed, Iftiin Hassan; Giorgio, Carmine; Russo, Simonetta; Bruni, Renato; Lelli, Barbara; Bracci, Luisa; Noberini, Roberta; Pasquale, Elena B.; Barocelli, Elisabetta; Vicini, Paola; Mor, Marco

    2012-01-01

    The Eph–ephrin system, including the EphA2 receptor and the ephrin-A1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3?,5?)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist able to inhibit EphA2 receptor activation and therefore potentially useful as a novel EphA2 receptor targeting agent. Here, we explore the structure-activity relationships of a focused set of lithocholic acid derivatives, based on molecular modelling investigation and displacement binding assays. Our exploration shows that while the 3-?-hydroxyl group of lithocholic acid has a negligible role in the recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrin-A1 to the EphA2. As a result of our investigation, we identified (5?)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits EphA2-ephrin-A1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand-binding domain of EphA2, with a steady-state dissociation constant (KD) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 and cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrin-A1 ligand. These findings suggest that cholanic acid can be used as a template structure to design effective EphA2 antagonists, with potential impact in the elucidation of the role played by this receptor in pathological conditions. PMID:22529030

  6. Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.

    PubMed

    Gunthorpe, Martin J; Hannan, Sara Luis; Smart, Darren; Jerman, Jeffrey C; Arpino, Sandra; Smith, Graham D; Brough, Stephen; Wright, Jim; Egerton, Julie; Lappin, Sarah C; Holland, Vicky A; Winborn, Kim; Thompson, Mervyn; Rami, Harshad K; Randall, Andrew; Davis, John B

    2007-06-01

    Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development. PMID:17392405

  7. Urinary responses to acute moxonidine are inhibited by natriuretic peptide receptor antagonist

    PubMed Central

    El-Ayoubi, Rouwayda; Menaouar, Ahmed; Gutkowska, Jolanta; Mukaddam-Daher, Suhayla

    2005-01-01

    We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. Moxonidine (0, 10, 50, 100 or 150??g in 300??l saline) and clonidine (0, 1, 5 or 10??g in 300??l saline) injected intravenously in conscious normally hydrated normotensive Sprague–Dawley rats (SD, ?200?g) and 12–14-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose-dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post-injection. The actions of 5??g clonidine and 50??g moxonidine were inhibited by yohimbine, an ?2-adrenoceptor antagonist, and efaroxan, an imidazoline I1-receptor antagonist. Moxonidine (100??g) stimulated (P<0.01) diuresis in SHR (0.21±0.04 vs 1.16±0.06?ml?h?1 100?g?1), SD (0.42±0.06 vs 1.56±0.19?ml?h?1 100?g?1) and WKY (0.12±0.04 vs 1.44±0.21?ml?h?1 100?g?1). Moxonidine-stimulated urine output was lower in SHR than in SD and WKY. Moxonidine-stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10??g) resulted in dose-dependent inhibition of moxonidine-stimulated urinary actions. Anantin (10??g) inhibited (P<0.01) urine output to 0.38±0.06, 0.12±0.01, and 0.16±0.04?ml?h?1 100?g?1 in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417±58 vs 1021±112?pg?ml?1) and WKY (309±59 vs 1433±187?pg?ml?1), and in SHR (853±96 vs 1879±229?pg?ml?1). These results demonstrate that natriuretic peptides mediate the urinary actions of moxonidine through natriuretic peptide receptors. PMID:15700025

  8. A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects.

    PubMed

    Bonaventure, Pascal; Yun, Sujin; Johnson, Philip L; Shekhar, Anantha; Fitz, Stephanie D; Shireman, Brock T; Lebold, Terry P; Nepomuceno, Diane; Lord, Brian; Wennerholm, Michelle; Shelton, Jonathan; Carruthers, Nicholas; Lovenberg, Timothy; Dugovic, Christine

    2015-03-01

    Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.1.0]hept-4-yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine]. Ex vivo receptor binding studies demonstrated that, after subcutaneous administration, compound 56 crossed the blood-brain barrier and occupied OX1Rs in the rat brain at lower doses than standard OX1R antagonists GSK-1059865 [5-bromo-N-({1-[(3-fluoro-2-methoxyphenyl)carbonyl]-5-methylpiperidin-2-yl}methyl)pyridin-2-amine], SB-334867 [1-(2-methyl-1,3-benzoxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea], and SB-408124 [1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea]. Although compound 56 did not alter spontaneous sleep in rats and in wild-type mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states. PMID:25583879

  9. Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo

    SciTech Connect

    Poulton, Emma Jane [Center for Ecogenetics and Environmental Health, University of Washington (United States) [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Environmental and Occupational Health Sciences, University of Washington (United States); Levy, Lisa [Public Health Sciences Division, Fred Hutchinson Cancer Research Center (United States)] [Public Health Sciences Division, Fred Hutchinson Cancer Research Center (United States); Lampe, Johanna W. [Center for Ecogenetics and Environmental Health, University of Washington (United States) [Center for Ecogenetics and Environmental Health, University of Washington (United States); Public Health Sciences Division, Fred Hutchinson Cancer Research Center (United States); Shen, Danny D. [Center for Ecogenetics and Environmental Health, University of Washington (United States) [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Pharmaceutics, University of Washington (United States); Tracy, Julia [Center for Ecogenetics and Environmental Health, University of Washington (United States) [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Environmental and Occupational Health Sciences, University of Washington (United States); Shuhart, Margaret C. [Division of Gastroenterology, Department of Medicine (United States)] [Division of Gastroenterology, Department of Medicine (United States); Thummel, Kenneth E. [Center for Ecogenetics and Environmental Health, University of Washington (United States) [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Pharmaceutics, University of Washington (United States); Eaton, David L., E-mail: deaton@uw.edu [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Environmental and Occupational Health Sciences, University of Washington (United States); Department of Pharmaceutics, University of Washington (United States)

    2013-01-01

    Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand — rifampicin (300 mg/d) was given alone for 7 days in arm 1, or in daily combination with 450 ?mol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. -- Highlights: ? The effects of SFN on PXR mediated CYP3A4 induction in humanized PXR mice and humans were examined. ? SFN had no effect on rifampicin mediated CYP3A4 induction in humans or humanized mice. ? SFN had a modest effect on basal CYP3A4 activity among subjects with higher baseline activity. ? Humanized PXR mice were generally predictive of the in vivo human response.

  10. A radioiodinated linear vasopressin antagonist: a ligand with high affinity and specificity for V1a receptors.

    PubMed

    Schmidt, A; Audigier, S; Barberis, C; Jard, S; Manning, M; Kolodziejczyk, A S; Sawyer, W H

    1991-04-22

    A linear vasopressin antagonist, Phaa-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (Linear AVP Antag) (Phaa = Phenylacetyl), was monoiodinated at the phenyl moiety of the tyrosylamide residue at position 9. This antagonist appeared to be a highly potent anti-vasopressor peptide with a pA2 value in vivo of 8.94. It was demonstrated to bind to rat liver membrane preparations with a very high affinity (Kd = 0.06 nM). The affinity for the rat uterus oxytocin receptor was lower (Ki = 2.1 nM), and affinities for the rat kidney- and adenohypophysis-vasopressin receptors were much lower (Ki = 47 nM and 92 nM, respectively), resulting in a highly specific vasopressin V1a receptor ligand. Autoradiographical studies using rat brain slices showed that this ligand is a good tool for studies on vasopressin receptor localization and characterization. PMID:1827414

  11. Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin.

    PubMed

    Manning, M; Bankowski, K; Barberis, C; Jard, S; Elands, J; Chan, W Y

    1992-01-01

    We report the solid phase synthesis of six analogs of the potent and selective linear AVP vasopressor (V1a receptor) antagonist: Phaa1-D-Tyr(Et)2-Phe3-Gln4-Asn5-Lys6-Pro7-Arg-NH(8)2(A) (where Phaa = phenylacetyl) in which the Phaa1 residue is replaced by hydroxyphenylacetyl (HO-Phaa), hydroxyphenylpropionyl (HO-Phpa) and phenylpropionyl (Phpa) and the D-Tyr(Et)2 and Lys6 residues by D-Tyr(Me)2 and Arg6 substituents. The phenolic-containing peptides were synthesized to test the feasibility of using this approach for the design of high affinity selective ligands for AVP V1a receptors. The following analogs of A were synthesized: 11 [(HO)Phaa1]; 2. [(HO)Phaa1,D-Tyr(Me)2]; 3. [(HO)Phaa1,D-Tyr(Me)2, Arg6]; 4. [(HO)Phaa1,Arg6]; 5. [Phpa1]; 6. [(HO)Phpa1]. All six peptides were examined for agonistic and antagonistic potencies in vasopressor (V1a-receptor) and antidiuretic (V2-receptor) and in vitro oxytocic assays in rats. The affinities of the phenolic-containing peptides for hepatic V1a and uterine receptors were also determined. The phenolic-containing peptides all exhibit potent V1a antagonism. Their anti-V1a pA2 values range from 8.23 to 8.63 (the anti-V1a pA2 value of A = 8.69). Their inhibition constants (Ki in nM) range 0.4 to 1.0. They are weak antidiuretic agonists with activities ranging from 0.022 U/mg to 0.13 U/mg (A = 0.033 U/mg). They all exhibit OT antagonism in vitro. Their anti-OT pA2 values range from 7.28 to 7.71 (A = 7.62). All five phenolic compounds were iodinated using iodine chloride and tested in the same in vivo and in vitro assay system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1478783

  12. Identification of Putative Steroid Receptor Antagonists in Bottled Water: Combining Bioassays and High-Resolution Mass Spectrometry

    PubMed Central

    Wagner, Martin; Schlüsener, Michael P.; Ternes, Thomas A.; Oehlmann, Jörg

    2013-01-01

    Endocrine disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling and thereby adversely affecting human health. Recent reports provide evidence for the presence of EDCs in commercially available bottled water, including steroid receptor agonists and antagonists. However, since these findings are based on biological data the causative chemicals remain unidentified and, therefore, inaccessible for toxicological evaluation. Thus, the aim of this study is to assess the antiestrogenic and antiandrogenic activity of bottled water and to identify the causative steroid receptor antagonists. We evaluated the antiestrogenic and antiandrogenic activity of 18 bottled water products in reporter gene assays for human estrogen receptor alpha and androgen receptor. Using nontarget high-resolution mass spectrometry (LTQ-Orbitrap Velos), we acquired corresponding analytical data. We combined the biological and chemical information to determine the exact mass of the tentative steroid receptor antagonist. Further MSn experiments elucidated the molecule’s structure and enabled its identification. We detected significant antiestrogenicity in 13 of 18 products. 16 samples were antiandrogenic inhibiting the androgen receptor by up to 90%. Nontarget chemical analysis revealed that out of 24520 candidates present in bottled water one was consistently correlated with the antagonistic activity. By combining experimental and in silico MSn data we identified this compound as di(2-ethylhexyl) fumarate (DEHF). We confirmed the identity and biological activity of DEHF and additional isomers of dioctyl fumarate and maleate using authentic standards. Since DEHF is antiestrogenic but not antiandrogenic we conclude that additional, yet unidentified EDCs must contribute to the antagonistic effect of bottled water. Applying a novel approach to combine biological and chemical analysis this is the first study to identify so far unknown EDCs in bottled water. Notably, dioctyl fumarates and maleates have been overlooked by science and regulation to date. This illustrates the need to identify novel toxicologically relevant compounds to establish a more holistic picture of the human exposome. PMID:24015248

  13. Identification of putative steroid receptor antagonists in bottled water: combining bioassays and high-resolution mass spectrometry.

    PubMed

    Wagner, Martin; Schlüsener, Michael P; Ternes, Thomas A; Oehlmann, Jörg

    2013-01-01

    Endocrine disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling and thereby adversely affecting human health. Recent reports provide evidence for the presence of EDCs in commercially available bottled water, including steroid receptor agonists and antagonists. However, since these findings are based on biological data the causative chemicals remain unidentified and, therefore, inaccessible for toxicological evaluation. Thus, the aim of this study is to assess the antiestrogenic and antiandrogenic activity of bottled water and to identify the causative steroid receptor antagonists. We evaluated the antiestrogenic and antiandrogenic activity of 18 bottled water products in reporter gene assays for human estrogen receptor alpha and androgen receptor. Using nontarget high-resolution mass spectrometry (LTQ-Orbitrap Velos), we acquired corresponding analytical data. We combined the biological and chemical information to determine the exact mass of the tentative steroid receptor antagonist. Further MS(n) experiments elucidated the molecule's structure and enabled its identification. We detected significant antiestrogenicity in 13 of 18 products. 16 samples were antiandrogenic inhibiting the androgen receptor by up to 90%. Nontarget chemical analysis revealed that out of 24520 candidates present in bottled water one was consistently correlated with the antagonistic activity. By combining experimental and in silico MS(n) data we identified this compound as di(2-ethylhexyl) fumarate (DEHF). We confirmed the identity and biological activity of DEHF and additional isomers of dioctyl fumarate and maleate using authentic standards. Since DEHF is antiestrogenic but not antiandrogenic we conclude that additional, yet unidentified EDCs must contribute to the antagonistic effect of bottled water. Applying a novel approach to combine biological and chemical analysis this is the first study to identify so far unknown EDCs in bottled water. Notably, dioctyl fumarates and maleates have been overlooked by science and regulation to date. This illustrates the need to identify novel toxicologically relevant compounds to establish a more holistic picture of the human exposome. PMID:24015248

  14. Crystal structure of a prolactin receptor antagonist bound to the extracellular domain of the prolactin receptor.

    PubMed

    Svensson, L Anders; Bondensgaard, Kent; Nørskov-Lauritsen, Leif; Christensen, Leif; Becker, Peter; Andersen, Mette D; Maltesen, Morten J; Rand, Kasper D; Breinholt, Jens

    2008-07-01

    The crystal structure of the complex between an N-terminally truncated G129R human prolactin (PRL) variant and the extracellular domain of the human prolactin receptor (PRLR) was determined at 2.5A resolution by x-ray crystallography. This structure represents the first experimental structure reported for a PRL variant bound to its cognate receptor. The binding of PRL variants to the PRLR extracellular domain was furthermore characterized by the solution state techniques, hydrogen exchange mass spectrometry, and NMR spectroscopy. Compared with the binding interface derived from mutagenesis studies, the structural data imply that the definition of PRL binding site 1 should be extended to include residues situated in the N-terminal part of loop 1 and in the C terminus. Comparison of the structure of the receptor-bound PRL variant with the structure reported for the unbound form of a similar analogue ( Jomain, J. B., Tallet, E., Broutin, I., Hoos, S., van Agthoven, J., Ducruix, A., Kelly, P. A., Kragelund, B. B., England, P., and Goffin, V. (2007) J. Biol. Chem. 282, 33118-33131 ) demonstrates that receptor-induced changes in the backbone of the four-helix bundle are subtle, whereas large scale rearrangements and structuring occur in the flexible N-terminal part of loop 1. Hydrogen exchange mass spectrometry data imply that the dynamics of the four-helix bundle in solution generally become stabilized upon receptor interaction at binding site 1. PMID:18467331

  15. Novel heterocyclic-substituted benzofuran histamine H 3 receptor antagonists: In vitro properties, drug-likeness, and behavioral activity

    Microsoft Academic Search

    Marlon Cowart; Gregory A. Gfesser; Kaitlin E. Browman; Ramin Faghih; Thomas R. Miller; Ivan Milicic; John L. Baranowski; Kathleen M. Krueger; David G. Witte; Angela L. Molesky; Victoria A. Komater; Michael J. Buckley; Gilbert J. Diaz; Gerard D. Gagne; Deliang Zhou; Xiaoqing Deng; Liping Pan; Ellen M. Roberts; Marilyn S. Diehl; Jill M. Wetter; Kennan C. Marsh; Gerard B. Fox; Jorge D. Brioni; Timothy A. Esbenshade; Arthur A. Hancock

    2007-01-01

    Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H3 receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H3 receptors, and when profiled in vivo for CNS activity, all were found active in an animal

  16. Effects of the novel 5HT 6 receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating

    Microsoft Academic Search

    Rudy Schreiber; Jef Vivian; Linda Hedley; Krystine Szczepanski; Rob L. Secchi; Marcus Zuzow; Susanne van Laarhoven; Jean-Luc Moreau; James R. Martin; Ayhan Sik; Arjan Blokland

    2007-01-01

    Serotonin6 (5-HT6) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT6 antagonists such as RO4368554 allows further characterization of the role of the 5-HT6 receptor in these processes. Herein, we tested RO4368554

  17. Effects of various nonopioid receptor antagonists on the antinociceptive activity of Muntingia calabura extracts in mice.

    PubMed

    Zakaria, Z A; Hassan, M H; Nurul Aqmar, M N H; Abd Ghani, M; Mohd Zaid, S N H; Sulaiman, M R; Hanan Kumar, G; Fatimah, C A

    2007-10-01

    This study was carried out in mice to determine the nonopioid receptor signaling pathway(s) that might modulate the antinociceptive activity of the aqueous and chloroform extracts of Muntingia calabura (M. calabura) leaves, using the hot-plate test. The leaves of M. calabura were sequentially soaked [1:2 (w/v); 72 h] in distilled water (dH(2)O) and chloroform. The 50% concentration extracts were selected for this study based on the plant's previously established antinociceptive profiles. The mice (n = 7) were pretreated (s.c.) for 10 min with the selected nonopioid receptor antagonists, followed by the (s.c.) administration of the respective extract. The latency of discomfort was recorded at the interval time of 0.5, 1, 2, 3, 4 and 5 h after the extract administration. The 5 mg/kg atropine, 10 mg/kg phenoxybenzamine, 10 mg/kg yohimbine, 10 mg/kg pindolol, 1 mg/kg haloperidol and 10 mg/kg bicuculline caused significant (p < 0.05) reduction in the aqueous extract-induced antinociceptive activity. The 10 mg/kg phenoxybenzamine, 10 mg/kg yohimbine, 10 mg/kg pindolol and 10 mg/kg bicuculline caused significant (p < 0.05) reduction in the chloroform extract-induced antinociceptive activity. In conclusion, the central antinociceptive activity of M. calabura leaves appears to be involved in the modulation of various nonopioid receptor signaling pathways. Its aqueous extract antinociceptive activity is mediated via modulation of the muscarinic, alpha(1)-adrenergic, alpha(2)-adrenergic, beta-adrenergic, dopaminergic and GABAergic receptors, while its chloroform extract activity is mediated via modulation of the alpha(1)-adrenergic, alpha(2)-adrenergic, beta-adrenergic and GABAergic receptors. PMID:18040526

  18. 3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists.

    PubMed

    Wei, Jing; Wang, Songqing; Gao, Shaofen; Dai, Xuedong; Gao, Qingzhi

    2007-01-01

    Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands. PMID:17330954

  19. IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING

    PubMed Central

    Teske, Kelly; Nandhikonda, Premchendar; Bogart, Jonathan W.; Feleke, Belaynesh; Sidhu, Preetpal; Yuan, Nina; Preston, Joshua; Goy, Robin; Han, Lanlan; Silvaggi, Nicholas R; Singh, Rakesh K.; Bikle, Daniel D.; Cook, James M.; Arnold, Leggy A.

    2014-01-01

    Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR) antagonists among nuclear receptor (NR) ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database”. Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR’s natural ligands 1,25(OH2)D3 and 25(OH2)D3. The first virtual screen identified 32 NR ligands with a calculate free energy of VDR binding of more than ?6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA) are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 µM. The second screen identified 162 NR ligands with a calculate free energy of VDR binding of more than ?6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ER?/? ligands (26%), TR?/? ligands (7%) and LxR?/? ligands (7%). The binding between VDR and ER? ligand H6036 as well as TR?/? ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization. PMID:25419525

  20. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium

    PubMed Central

    2011-01-01

    Background Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. Results Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. Conclusion Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons. PMID:21859486

  1. 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 (Michigan-Med); (Stanford-MED); (UAB, Spain)

    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.

  2. Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma

    PubMed Central

    Wolter, Jennifer K; Wolter, Nikolaus E; Blanch, Alvaro; Partridge, Teresa; Cheng, Lynn; Morgenstern, Daniel A.; Podkowa, Monika; Kaplan, David R.; Irwin, Meredith S.

    2014-01-01

    Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective ?-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the ?2, and not ?1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express ?2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB. PMID:24389287

  3. Studies on an (S)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

    PubMed Central

    Juknait?, Lina; Sugamata, Yutaro; Tokiwa, Kazuya; Ishikawa, Yuichi; Takamizawa, Satoshi; Eng, Andrew; Sakai, Ryuichi; Pickering, Darryl S.; Frydenvang, Karla; Swanson, Geoffrey T.; Kastrup, Jette S.; Oikawa, Masato

    2015-01-01

    IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. PMID:23432124

  4. History and Perspectives of A2A Adenosine Receptor Antagonists as Potential Therapeutic Agents.

    PubMed

    Preti, Delia; Baraldi, Pier Giovanni; Moorman, Allan R; Borea, Pier Andrea; Varani, Katia

    2015-07-01

    Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD. PMID:25821194

  5. The clinically available NMDA receptor antagonist, memantine, exhibits relative safety in the developing rat brain.

    PubMed

    Manning, Simon M; Boll, Griffin; Fitzgerald, Erin; Selip, Debra B; Volpe, Joseph J; Jensen, Frances E

    2011-11-01

    The N-methyl-d-aspartate glutamate receptor (NMDAR) has been implicated in preterm brain injury (periventricular leukomalacia (PVL)) and represents a potential therapeutic target. However, the antagonist dizocilpine (MK-801) has been reported to increase constitutive neuronal apoptosis in the developing rat brain, limiting its clinical use in the developing brain. Memantine is another use-dependent NMDAR antagonist with shorter binding kinetics and has been demonstrated to be protective in a rat model of PVL, without effects on normal myelination or cortical growth. To further evaluate the safety of memantine in the developing brain, we demonstrate here that, in contrast to MK-801, memantine at neuroprotective doses does not increase neuronal constitutive apoptosis. In addition, there are no long-term alterations in the expression of NMDAR subunits, AMPAR subunits, and two markers of synaptogenesis, Synapsin-1 and PSD95. Evaluating clinically approved drugs in preclinical neonatal animal models of early brain development is an important prerequisite to considering them for clinical trial in preterm infants and early childhood. PMID:21624454

  6. A 3D QSAR approach to the search for geometrical similarity in a series of nonpeptide angiotensin II receptor antagonists

    Microsoft Academic Search

    Laura Belvisi; Gianpaolo Bravi; Carlo Scolastico; Anna Vulpetti; Aldo Salimbeni; Roberto Todeschini

    1994-01-01

    A 3D QSAR methodology based on the combined use of conformational analysis and chemometrics was applied to perform a comparative analysis of the 3D conformational features of 13 nonpeptide angiotensin II receptor antagonists showing different levels of binding affinity. Conformational analysis by using a molecular mechanics MM2 method was carried out for each of these structures to obtain conformational minima.

  7. Effect of the NMDA receptor antagonist MK-801 on recovery from spinal cord injury in rats given uncontrollable stimulation

    E-print Network

    Petrich, Christine

    2006-08-16

    , were given the NMDA receptor antagonist MK-801 (0.08 mg/kg, i.p.) or its vehicle before receiving either a bout of uncontrollable stimulation or identical treatment without the stimulation itself. Their hindlimb motor activity was monitored for 21 days...

  8. Spatial Discrimination Reversal Learning in Weanling Rats Is Impaired by Striatal Administration of an NMDA-Receptor Antagonist

    ERIC Educational Resources Information Center

    Watson, Deborah J.; Stanton, Mark E.

    2009-01-01

    The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801…

  9. The Position of Pranlukast, a Cysteinyl Leukotriene Receptor Antagonist, in the Long-Term Treatment of Asthma

    Microsoft Academic Search

    Yasushi Obase; Terufumi Shimoda; Hiroto Matsuse; Yuki Kondo; Ikuko Machida; Tetsuya Kawano; Sachiko Saeki; Shinya Tomari; Kazuko Mitsuta-Izaki; Nobuko Matsuo; Chizu Fukushima; Shigeru Kohno

    2004-01-01

    Background: Adverse effects, tachyphylaxis, and the position of pranlukast, a cysteinyl leukotriene receptor antagonist, in asthma treatment have not been fully established. Objectives and Methods: To address these questions, adverse effects and long-term efficacy of pranlukast were evaluated in 82 patients [28 patients with moderate asthma (group I), 27 with severe persistent asthma not on oral corticosteroid (OCS; group II)

  10. The Analgesic Interaction Between Intrathecal Clonidine and Glutamate Receptor Antagonists on Thermal and Formalin-Induced Pain in Rats

    Microsoft Academic Search

    Tomoki Nishiyama; Laszlo Gyermek; Chingmuh Lee; Sachiko Kawasaki-Yatsugi; Tokio Yamaguchi; Kazuo Hanaoka

    2001-01-01

    Clonidine, an a2 adrenergic receptor agonist, inhibits gluta- mate release from the spinal cord. We studied the interaction ofintrathecallyadministeredclonidineandglutamaterecep- tor antagonists on acute thermal or formalin induced noci- ception. Sprague-Dawley rats with lumbar intrathecal cath- eters were tested for their tail withdrawal response by the tail flick test and paw flinches produced by formalin injection after intrathecal administration of saline,

  11. Antagonistic TNF Receptor One-Specific Antibody (ATROSAB): Receptor Binding and In Vitro Bioactivity

    PubMed Central

    Richter, Fabian; Liebig, Timo; Guenzi, Eric; Herrmann, Andreas; Scheurich, Peter; Pfizenmaier, Klaus; Kontermann, Roland E.

    2013-01-01

    Background Selective inhibition of TNFR1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, while leaving TNFR2 untouched, thus allowing for cell survival and tissue homeostasis. ATROSAB is a humanized antagonistic anti-TNFR1 antibody developed for the treatment of inflammatory diseases. Methodology/Principal Findings The epitope of ATROSAB resides in the N-terminal region of TNFR1 covering parts of CRD1 and CRD2. By site-directed mutagenesis, we identified Arg68 and His69 of TNFR1 as important residues for ATROSAB binding. ATROSAB inhibited binding of 125I-labeled TNF to HT1080 in the subnanomolar range. Furthermore, ATROSAB inhibited release of IL-6 and IL-8 from HeLa and HT1080 cells, respectively, induced by TNF or lymphotoxin alpha (LT?). Different from an agonistic antibody (Htr-9), which binds to a region close to the ATROSAB epitope but elicits strong TNFR1 activation, ATROSAB showed a negligible induction of IL-6 and IL-8 production over a broad concentration range. We further verified that ATROSAB, comprising mutations within the Fc region known to abrogate complement fixation and antibody-mediated cellular effector functions, indeed lacks binding activity for C1q, Fc?RI (CD64), Fc?RIIB (CD32b), and Fc?RIII (CD16) disabling ADCC and CDC. Conlusions/Significance The data corroborate ATROSAB’s unique function as a TNFR1-selective antagonist efficiently blocking both TNF and LT? action. In agreement with recent studies of TNFR1 complex formation and activation, we suggest a model of the underlying mechanism of TNFR1 inhibition by ATROSAB. PMID:23977237

  12. Excitatory amino acid receptor subtype agonists induce feeding in the nucleus accumbens shell in rats: opioid antagonist actions and interactions with ?-opioid agonists

    Microsoft Academic Search

    Joyce A Echo; Nicole Lamonte; Garrison Christian; Vladimir Znamensky; Tsippa F Ackerman; Richard J Bodnar

    2001-01-01

    Administration of ?-opioid receptor subtype agonists into the nucleus accumbens shell elicits feeding which is dependent upon the normal function of ?-, ?- and ?-opioid receptors, D1 dopamine receptors and GABAB receptors in the nucleus accumbens shell for its full expression. Whereas the AMPA antagonist, DNQX administered into the nucleus accumbens shell elicits a transient, though intense feeding response, feeding

  13. Discovery of Selective Probes and Antagonists for G Protein-Coupled Receptors FPR/FPRL1 and GPR30

    PubMed Central

    Arterburn, Jeffrey B.; Oprea, Tudor I.; Prossnitz, Eric R.; Edwards, Bruce S.; Sklar, Larry A.

    2010-01-01

    Recent technological advances in flow cytometry provide a versatile platform for high throughput screening of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. The complex biology and potential for drug discovery within this class provide strong incentives for chemical biology approaches seeking to develop small molecule probes to facilitate elucidation of mechanistic pathways and enable specific manipulation of the activity of individual receptors. We have initiated small molecule probe development projects targeting two distinct families of GPCRs: the formylpeptide receptors (FPR/FPRL1) and G protein-coupled estrogen receptor (GPR30). In each case the assay for compound screening involved the development of an appropriate small molecule fluorescent probe, and the flow cytometry platform provided inherently biological rich assays that enhanced the process of identification and optimization of novel antagonists. The contributions of cheminformatics analysis tools, virtual screening, and synthetic chemistry in synergy with the biomolecular screening program have yielded valuable new chemical probes with high binding affinity, selectivity for the targeted receptor, and potent antagonist activity. This review describes the discovery of novel small molecule antagonists of FPR and FPRL1, and GPR30, and the associated characterization process involving secondary assays, cell based and in vivo studies to define the selectivity and activity of the resulting chemical probes PMID:19807662

  14. Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy

    PubMed Central

    Deshpande, Laxmikant S.; Sombati, Sompong; Blair, Robert E.; Carter, Dawn S.; Martin, Billy R.; DeLorenzo, Robert J.

    2007-01-01

    Status epilepticus is a major medical emergency associated with a significant morbidity and mortality. Little is known about the mechanisms that terminate seizure activity and prevent the development of status epilepticus. Cannabinoids possess anticonvulsant properties and the endocannabinoid system has been implicated in regulating seizure duration and frequency. Endocannabinoids regulate synaptic transmission and dampen seizure activity via activation of the presynaptic cannabinoid receptor 1 (CB1). This study was initiated to evaluate the role of CB1 receptor-dependent endocannabinoid synaptic transmission towards preventing the development of status epilepticus-like activity in the well-characterized hippocampal neuronal culture model of acquired epilepsy using patch clamp electrophysiology. Application of the CB1 receptor antagonists SR141716A (1 ?M) or AM251 (1 ?M) to “epileptic” neurons caused the development of continuous epileptiform activity, resembling electrographic status epilepticus. The induction of status epilepticus-like activity by CB1 receptor antagonists was reversible and could be overcome by maximal concentrations of CB1 agonists. Similar treatment of control neurons with CB1 receptor antagonists did not produce status epilepticus or hyperexcitability. These findings suggest that CB1 receptor-dependent endocannabinoid endogenous tone plays an important role in modulating seizure frequency and duration and preventing the development of status epilepticus-like activity in populations of epileptic neurons. The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges. PMID:17110038

  15. Association of interleukin-1 receptor antagonist gene polymorphism and susceptibility to human brucellosis.

    PubMed

    Hajilooi, M; Rafiei, A; Reza Zadeh, M; Tajik, N

    2006-10-01

    The aim of this study was to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1Ra) on the susceptibility to or development of brucellosis. A total of 255 patients with brucellosis and 162 healthy volunteers were genotyped for polymorphisms in intron 2 of the IL-1Ra gene. The frequency of allele 2 of the IL-1Ra gene was significantly higher in patients with brucellosis compared with the controls (24.5% vs 18.5%, P = 0.03). Although the heterozygosity was more prevalent in patients than in control individuals, it did not have any statistical significance (P = 0.1). Alleles 3, 4, and 5 were absent in our study population. This work is the first that verifies a significant association between genetic polymorphism of IL-1Ra and susceptibility to brucellosis. PMID:17026469

  16. Effects of the kappa opioid receptor antagonist MR-2266-BS on the acquisition of ethanol preference

    SciTech Connect

    Sandi, C.; Borrell, J.; Guaza, C. (Cajal Institute, Madrid (Spain))

    1990-01-01

    Using a paradigm by which rats forced to drink a weak ethanol solution develop ethanol preference in consecutive retention testing days, the effects of the administration of the kappa opioid antagonist MR-2266-BS, prior to or after the forced ethanol session, were studied. Pre-conditioning subcutaneous (s.c.) administration of 1 mg/kg of MR-2266-BS induced a decrease in subsequent ethanol consumption without significantly modifying the acquisition of ethanol preference. Post-conditioning administration of MR-2266-BS induced both a dose-dependent reduction in ethanol consumption and in preference throughout the three following days. The results of the present study provide further support of the involvement of kappa-type opioids on drinking behavior, and suggest that kappa receptors may be involved in the consumption and development of preference to ethanol.

  17. The crystal structure of a bimorphinan with highly selective kappa opioid receptor antagonist activity

    NASA Astrophysics Data System (ADS)

    Urba?czyk-Lipkowska, Zofia; Etter, Margaret C.; Lipkowski, Andrzej W.; Portoghese, Philip S.

    1987-07-01

    The crystal structure of the dihydrobromide heptahydrate of nor-binaltorphimine (17, 17'-bis(cyclopropylmethyl)-6,6',7,7'-tetrahydro-4,5?: 4',5'?-diepoxy-6,6'-imino[7,7' bimorphinan]-3,3',14,14'-tetraol)is presented. This structure is the first reported structure of a rigid bivalent opioid ligand. Two morphinan pharmacophores are connected by a rigid spacer, the pyrrole ring. The nor-binaltorphimine structure itself shows unique, high selectivity as a kappa opioid receptor antagonist. Crystal data: P3 2, Z = 3, a = b = 20.223 (4), c = 9.541(7) Å, ? = ? = 90°, ? = 120°; R = 0.079 (1765 reflections, Fobs > 1?( F)).

  18. Recombinant human interleukin receptor antagonist influences serum chemokines in patients with rheumatoid arthritis

    PubMed Central

    Bao, Jun; Liu, Wei

    2014-01-01

    Objective To investigate the serum expressions of chemokines CCL2 and CCL3 in patients with rheumatoid arthritis (RA) who were treated with recombinant human interleukin 1 (IL-1) receptor antagonist (IL-1Ra). Material and methods Serum CCL2 and CCL3 were determined using an enzyme-linked immunosorbent assay in 54 active RA patients before and after treatment with IL-1Ra or a placebo, as well as 36 healthy controls. Results Compared with the healthy controls, all the 54 RA patients exhibited higher serum CCL2 and CCL3 before and after treatment (p < 0.05). However, patients who had a good response to IL-1Ra treatment had significantly lower mean changes in the serum CCL2 and CCL3 levels from baseline to the last injection than IL-1Ra non-responders (p < 0.01). Conclusions CCL2 and CCL3 may be useful efficacy markers of IL-1Ra treatment.

  19. An androgen receptor N-terminal domain antagonist for treating prostate cancer.

    PubMed

    Myung, Jae-Kyung; Banuelos, Carmen A; Fernandez, Javier Garcia; Mawji, Nasrin R; Wang, Jun; Tien, Amy H; Yang, Yu Chi; Tavakoli, Iran; Haile, Simon; Watt, Kate; McEwan, Iain J; Plymate, Stephen; Andersen, Raymond J; Sadar, Marianne D

    2013-07-01

    Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents. PMID:23722902

  20. Acute Inhibition of Selected Membrane-Proximal Mouse T Cell Receptor Signaling by Mitochondrial Antagonists

    PubMed Central

    Hwang, Inkyu

    2009-01-01

    T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR) with cognate peptide/major histocompatibility complex (MHC) plus lymphocyte function-associated antigen 1 (LFA-1) with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS) platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour) with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin), resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s). Thus, activation of Akt and PLC-?1 and entry of extracellular Ca2+ following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption) could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours) on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function. PMID:19901985

  1. Polymorphisms of interleukin-1R receptor antagonist genes in patients with chronic hepatitis B in Iran

    PubMed Central

    Ranjbar, Mitra; Alizadeh, Amir Houshang Mohammad; Hajilooi, Mehrdad; Mousavi, Seyed Mohsen

    2006-01-01

    AIM: To investigate the relationships between polymorphisms of interleukin-1R receptor antagonist genes and susceptibility to chronic hepatitis B in Iran population. METHODS: Genomic DNA was extracted from the peripheral blood of 80 patients with chronic hepatitis B (57 males, 23 females) aged 12-77 years (mean 36.1 ± 13.8 years) and 147 normal controls (96 males, 51 females) aged 6-75 years (mean 41 ± 18.7 years) who referred to a liver clinic of Tehran and then subjected to polymerase chain reaction (PCR) amplification. PCR products were resolved on a 3% agarose gel and stained with ethidium bromide. RESULTS: Only three of the five kinds of polymorphism (2/2, 2/4, and 4/4) were found in this study. The frequencies of 2/2, 2/4, and 4/4 were 12.5%, 17.5%, 70% respectively in chronic hepatitis B patients and 6.8%, 24.5%, and 68.7% respectively in controls. IL-1 R allele 2 was detected in 30% of chronic hepatitis B patients and in 31.3% of controls, while IL-1 R allele 4 was detected in 87.5% of chronic hepatitis B patients and in 93.2% of controls. The frequency of IL-1R alleles 2 and 4 was detected in 21.25% and 78.75% of the patients and 19.04% and 80.96% of the controls, respectively. CONCLUSION: Our results suggest that the carriage of IL-1R receptor antagonist alleles 2, 4, 6 may not play any role in the development of HBV infection. Large population-based studies are needed to investigate the role of IL-1 polymorphisms in the pathogenesis of developing chronic hepatitis B. PMID:16937503

  2. Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-?/? Antagonist GSK3787S?

    PubMed Central

    Palkar, Prajakta S.; Borland, Michael G.; Naruhn, Simone; Ferry, Christina H.; Lee, Christina; Sk, Ugir H.; Sharma, Arun K.; Amin, Shantu; Murray, Iain A.; Anderson, Cherie R.; Perdew, Gary H.; Gonzalez, Frank J.; Müller, Rolf

    2010-01-01

    The availability of high-affinity agonists for peroxisome proliferator-activated receptor-?/? (PPAR?/?) has led to significant advances in our understanding of the functional role of PPAR?/?. In this study, a new PPAR?/? antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (GW0742)-induced up-regulation of Angptl4 and Adrp mRNA expression in wild-type mouse colon but not in Ppar?/?-null mouse colon. Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of PPAR?/? on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of PPAR?/? activity and weak antagonism and agonism of PPAR? activity but no effect on PPAR? activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of GSK3787 to modulate the association of both PPAR?/? and PPAR? coregulator peptides in response to ligand activation, consistent with reporter assays. In vivo and in vitro analysis indicates that the efficacy of GSK3787 to modulate PPAR? activity is markedly lower than the efficacy of GSK3787 to act as a PPAR?/? antagonist. GSK3787 antagonized GW0742-induced expression of Angptl4 in mouse fibroblasts, mouse keratinocytes, and human cancer cell lines. Cell proliferation was unchanged in response to either GW0742 or GSK3787 in human cancer cell lines. Results from these studies demonstrate that GSK3787 can antagonize PPAR?/? in vivo, thus providing a new strategy to delineate the functional role of a receptor with great potential as a therapeutic target for the treatment and prevention of disease. PMID:20516370

  3. Brain changes associated with thromboxane receptor antagonist SQ 29,548 treatment in a mouse model.

    PubMed

    Rebel, Andrew A; Urquhart, Siri A; Puig, Kendra L; Ghatak, Atreyi; Brose, Stephen A; Golovko, Mikhail Y; Combs, Colin K

    2015-08-01

    The purpose of this study was to characterize behavioral and physiological effects of a selective thromboxane (TP) receptor antagonist, SQ 29,548, in the C57Bl/6 mouse model. At 6 months of age, male mice were given either sham or drug i.p. injections for 3 days at a dose of 2 mg/kg each day. On the day after the final injection, mice were subjected to behavioral testing before brain collection. Left hemisphere hippocampi were collected from all mice for protein analysis via Western blot. Right brain hemispheres were fixed and embedded in gelatin and then serially sectioned. The sections were immunostained with anti-c-Fos antibodies. Prostaglandin analysis was performed from remaining homogenized brain samples, minus the hippocampi. Injection of SQ 29,548 decreased selective brain prostaglandin levels compared with sham controls. This correlated with robust increases in limbic-region c-Fos immunoreactivity in the SQ 29,548-injected mice. However, drug-treated mice demonstrated no significant changes in relevant hippocampal protein levels compared with sham treatments, as determined from Western blots. Surprisingly, injection of SQ 29,548 caused mixed changes in parameters of depression and anxiety-like behavior in the mice. In conclusion, the results indicate that administration of peripheral TP receptor antagonists alters brain levels of prostanoids and influences neuronal activity, with only minimal alterations of behavior. Whether the drug affects neurons directly or through a secondary pathway involving endothelium or other tissues remains unclear. © 2015 Wiley Periodicals, Inc. PMID:25703023

  4. Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP67580.

    PubMed Central

    Rupniak, N. M.; Boyce, S.; Williams, A. R.; Cook, G.; Longmore, J.; Seabrook, G. R.; Caeser, M.; Iversen, S. D.; Hill, R. G.

    1993-01-01

    1. Release of substance P in the dorsal horn is considered a primary event in the perception of pain. The profile of racemic RP67580, a non-peptide antagonist at the NK1 (substance P) receptor, was examined in a range of antinociception tests on rodents. 2. At doses up to 30 mg kg-1, s.c. racemic RP67580 exhibited antinociceptive activity in writhing and formalin paw tests in mice and gerbils. Acetic acid induced writhing and the licking response to formalin were reduced to 40-50% of the level observed in vehicle-treated animals (P < 0.05). However, this agent was not active in mouse tail flick, rat paw pressure or rat and guinea-pig formalin paw tests. 3. Like racemic RP67580, the calcium channel blockers nifedipine (30 mg kg-1, i.p.) and verapamil (10 or 20 mg kg-1, s.c.) inhibited the response to formalin by approximately 60% in gerbils (P < 0.05 compared with vehicle-treated animals). 4. Evidence for calcium channel antagonist activity of RP67580 was obtained in vitro. Racemic RP67580 inhibited calcium entry into depolarized strips of guinea-pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 +/- 115 nM), inhibited [3H]-diltiazem binding to rabbit skeletal membranes (IC50 = 298 nM) and depressed high threshold calcium currents in neurones cultured from rat cortex (10% inhibition at 10 microM). 5. These findings indicate that the acute antinociceptive effects of RP67580 may not be attributable to a specific interaction with NK1 receptors and may be mediated via calcium channel blockade. PMID:8306108

  5. Design of novel chimeric melanotropin-deltorphin analogues. Discovery of the first potent human melanocortin 1 receptor antagonist.

    PubMed

    Han, G; Quillan, J M; Carlson, K; Sadée, W; Hruby, V J

    2003-02-27

    A number of novel alpha-melanotropin (alpha-MSH) analogues have been designed, synthesized, and assayed for bioactivity at the melanocortin-1 (MC1) receptor from Xenopus frog skin, and selected potent analogues were examined at recombinant human MC1, MC3, and MC4 receptors expressed in human embryonic kidney (HEK) cells. These ligands were designed from Deltorphin-II, by a new hybrid approach, which incorporates the hydrophobic tail and the address sequence of Deltorphin-II (Glu-Val-Val-Gly-NH(2)) and key pharmacophore elements of melanotropins. Some of the ligands designed, c[Xxx-Yyy-Zzz-Arg-Trp-Glu]-Val-Val-Gly-NH(2) [XXX = nothing, Gly, beta-Ala, gamma-Abu, 6-Ahx; YYY = His, His(3-Bom), (S)-cyclopentylglycine (Cpg); ZZZ = Phe, d-Phe; d-Nal(2')], show high potency at melanocortin receptors. One ligand, GXH-32B-c[beta-Ala-His-d-Nal(2')-Arg-Trp-Glu]-Val-Val-Gly-NH(2), the most potent of the chimeric analogues tested, displayed agonist activity at each of the MC receptor subtypes analyzed, with an EC(50) of 2 nM at the amphibian MC1 receptor. In contrast, GXH-38B-c[Gly-Cpg-d-Nal(2')-Arg-Trp-Glu]-Val-Val-Gly-NH(2) (Cpg = cyclopentyl glycine) was an antagonist with a IC(50) of 43 nM at the amphibian receptor, and among the human subtypes tested, was the most potent at the MC1 receptor subtype where it also acted as an antagonist (K(i) = 53 nM), which is the first potent antagonist discovered for the human MC1 receptor. These results provide strong evidence supporting our hypothesis that ligand scaffolds for different G-protein coupled receptors (GPCRs) can be used to design ligands for other GPCRs and to design more potent ligands to treat diseases associated with the human MC1 receptor. PMID:12593660

  6. Cardiovascular and behavioural effects of intracerebroventricularly administered tachykinin NK3 receptor antagonists in the conscious rat

    PubMed Central

    Cellier, Eric; Barbot, Lionel; Regoli, Domenico; Couture, Réjean

    1997-01-01

    In the conscious rat, three tachykinin NK3 receptor antagonists, namely SR142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), R820 (3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) and R486 (H-Asp-Ser-Phe-Trp-?-Ala-Leu-Met-NH2) were assessed against the intracerebroventricular (i.c.v.) effects induced by senktide, a selective NK3 receptor agonist, on mean arterial blood pressure (MAP), heart rate (HR) and motor behaviour. Senktide (10–650?pmol per animal; i.c.v; n=4–16) at the lowest dose caused a significant fall in MAP (?10±6?mmHg), while at the highest doses (100 and 650?pmol), senktide caused a rise in MAP (9±3 and 12±1?mmHg, respectively) when compared to vehicle. The intermediate doses (25 and 65?pmol) had no effect on MAP. The highest two doses caused a tachycardia of 62±15 and 88±8 beats min?1, respectively. The dose of 65?pmol had a biphasic effect on HR, an initial bradycardia of 47±12 beats min?1 followed by a tachycardia of 46±14 beats min?1. The lowest doses caused either a rise of 52±10 beats min?1 (25?pmol) or no effect (10?pmol) on HR. All doses of senktide caused similar increases in face washing, sniffing and wet dog shakes except at the dose of 100?pmol, when wet dog shakes were more than double those observed with the other doses. The antagonist SR142801 (100?pmol–65?nmol per animal; i.c.v.; n=6–8) caused increases in MAP at the highest two doses (6.5 and 65?nmol) while HR, dose-dependently, increased (23±6 to 118±26 beats min?1) and the onset dose-dependently decreased. The (R)-enantiomer, SR142806 (100?pmol–65?nmol per animal; i.c.v.; n=6–8) only caused rises in MAP (13±2?mmHg) and HR (69±11 beats min?1) at the highest dose. These drugs had no apparent effect on behaviour, except for the highest dose of SR142801 which increased sniffing. The antagonist R820 (650?pmol–6.5?nmol per animal; i.c.v.; n=6) had no effect on MAP or HR and only increased sniffing behaviour at 6.5?nmol. At 650?pmol (n=6), R486 had no effect on any variable, but at 3.25?nmol, i.c.v. (n=4) a delayed tachycardia and a significant increase in all behavioural variables were observed. The cardiovascular responses induced by 6.5?nmol SR142801 and 25?pmol senktide were inhibited by R820 (6.5?nmol, 5?min earlier i.c.v.). In contrast, R820 failed to affect the central cardiovascular and behavioural responses induced by 10?pmol [Sar9, Met(O2)11]substance P, a NK1 receptor selective agonist. The senktide-induced behavioural changes were not inhibited by R820 (6.5?nmol, i.c.v.) while R486 (650?pmol, i.c.v.) blocked both the cardiovascular and behavioural responses to 25?pmol senktide. A mixture of antagonists for NK1 (RP67580; 6.5?nmol) and NK2 (SR48968; 6.5?nmol) receptors injected i.c.v. did not affect the cardiovascular response to SR142801. Cross-desensitization was shown between the central responses to SR142801 and senktide, but not between SR142801 and [Sar9, Met(O2)11]substance P. The antagonists SR142801 and SR142806 (6.5–650?nmol?kg?1; n=5–7), given i.v., did not evoke any cardiovascular or behavioural changes, except a delayed bradycardia for SR142806 (650?nmol?kg?1), and also failed to inhibit the increase in MAP evoked by senktide (4?nmol?kg?1, i.v.). However, at the highest dose, both drugs slightly reduced the senktide-induced tachycardia. Although the present data are consistent with the in vitro pharmacological bioassays and binding data, showing that SR142801 is a poor antagonist at rat peripheral NK3 receptors, they suggest that SR142801 has a partial agonist action at these receptors centrally. A separation of the cardi

  7. Docking of linear peptide antagonists into the human V(1a) vasopressin receptor. Identification of binding domains by photoaffinity labeling.

    PubMed

    Phalipou, S; Seyer, R; Cotte, N; Breton, C; Barberis, C; Hibert, M; Mouillac, B

    1999-08-13

    A novel photoactivatable linear peptide antagonist selective for the V(1a) vasopressin receptor, [(125)I][Lys(3N(3) Phpa)(8)]HO-LVA, was synthesized, characterized, and used to photolabel the human receptor expressed in Chinese hamster ovary cells. Two specific glycosylated protein species at 85-90 and 46 kDa were covalently labeled, a result identical to that obtained with a previous photosensitive ligand, [(125)I]3N(3)Phpa-LVA (Phalipou, S., Cotte, N. , Carnazzi, E., Seyer, R., Mahe, E., Jard, S., Barberis, C., and Mouillac, B. (1997) J. Biol. Chem. 272, 26536-26544). To identify contact sites between the new photoreactive analogue and the V(1a) receptor, the labeled receptors were digested with Lys-C or Asp-N endoproteinases and chemically cleaved with CNBr. Fragmentation with CNBr, Lyc-C, and Asp-N used alone or in combination, led to the identification of a restricted receptor region spanning the first extracellular loop. The results established that sequence Asp(112)-Pro(120) could be considered as the smallest covalently labeled fragment with [(125)I][Lys(3N(3)Phpa)(8)]HO-LVA. Based on the present experimental result and on previous photoaffinity labeling data obtained with [(125)I]3N(3)Phpa-LVA (covalent attachment to transmembrane domain VII), three-dimensional models of the antagonist-bound receptors were constructed and then verified by site-directed mutagenesis studies. Strikingly, these two linear peptide antagonists, when bound to the V(1a) receptor, could adopt a pseudocyclic conformation similar to that of the cyclic agonists. Despite divergent functional properties, these peptide antagonists could interact with a transmembrane-binding site significantly overlapping that of the natural hormone vasopressin. PMID:10438508

  8. ?3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure.

    PubMed

    Masutani, Satoshi; Cheng, Heng-Jie; Morimoto, Atsushi; Hasegawa, Hiroshi; Han, Qing-Hua; Little, William C; Cheng, Che Ping

    2013-09-15

    In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of ?3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. ?3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac ?3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 ?g/kg iv), a selective ?3-adrenergic receptor antagonist (?3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (?) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after ?3-ANT caused similar increases in heart rate and PES but significantly decreased ? (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, ?3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance. PMID:23873794

  9. Antidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review

    PubMed Central

    Drevets, Wayne C.; Zarate, Carlos A.; Furey, Maura L.

    2014-01-01

    The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine's pharmacokinetic properties and an emerging literature that characterizes scopolamine's effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 ?g/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism. PMID:23200525

  10. Effects of a Cysteinyl Leukotriene Dual 1\\/2 Receptor Antagonist on Antigen-Induced Airway Hypersensitivity and Airway Inflammation in a Guinea Pig Asthma Model

    Microsoft Academic Search

    Masato Muraki; Shu Imbe; Hiroshi Santo; Ryuji Sato; Hiroyuki Sano; Takashi Iwanaga; Yuji Tohda

    2011-01-01

    Background: Little is known about the role of the cysteinyl leukotriene (cysLT) 2 receptor in the pathophysiology of asthma. The aim of this study is to investigate the effects of a cysLT1 receptor antagonist (montelukast) and a dual cysLT1\\/2 receptor antagonist (BAY-u9773) on airway hypersensitivity and airway inflammation induced by antigen challenge in ovalbumin (OVA)-sensitized guinea pigs. Methods: Male Hartley

  11. Structure-activity relationships and optimization of 3,5-dichloropyridine derivatives as novel P2X(7) receptor antagonists.

    PubMed

    Lee, Won-Gil; Lee, So-Deok; Cho, Joong-Heui; Jung, Younghwan; Kim, Jeong-hyun; Hien, Tran T; Kang, Keon-Wook; Ko, Hyojin; Kim, Yong-Chul

    2012-04-26

    Screening of a library of chemical compounds showed that the dichloropyridine-based analogue 9 was a novel P2X(7) receptor antagonist. To optimize its activity, we assessed the structure-activity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton, and the hydrophobic acyl (R(2)) group. We found that the hydrazide linker and the 3,5-disubstituted chlorides in the pyridine skeleton were critical for P2X(7) antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R(2) position optimized antagonistic activity. In the EtBr uptake assay in hP2X(7)-expressing HEK293 cells, the optimized antagonists, 51 and 52, had IC(50) values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1?, by LPS/IFN-?/BzATP stimulation of THP-1 cells (IC(50) = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogues may be useful in developing P2X(7) receptor targeted anti-inflammatory agents. PMID:22400713

  12. A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

    Microsoft Academic Search

    Juan M Saavedra; Ines Armando; Claudia Bregonzio; Augusto Juorio; Miroslava Macova; Jaroslav Pavel; Enrique Sanchez-Lemus

    2006-01-01

    Long-term pretreatment with an angiotensin II AT1 antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic–pituitary–adrenal responses to isolation stress. We determined whether AT1 receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar

  13. Expression of IL1?, IL1 Receptor Type I and IL1 Receptor Antagonist in Human Aortic Smooth Muscle Cells: Effects of all-trans-Retinoic Acid

    Microsoft Academic Search

    Dick Wågsäter; Ken Jatta; Pauline Ocaya; Jan Dimberg; Allan Sirsjö

    2006-01-01

    The proinflammatory cytokine interleukin (IL)-1? and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1? levels

  14. S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

    SciTech Connect

    Vikram, Ajit [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India)] [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India); Jena, Gopabandhu, E-mail: gbjena@gmail.com [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India)] [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India)

    2010-07-23

    Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

  15. Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid?X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism.

    PubMed

    Huang, Huang; Si, Pei; Wang, Lei; Xu, Yong; Xu, Xin; Zhu, Jin; Jiang, Hualiang; Li, Weihua; Chen, Lili; Li, Jian

    2015-07-01

    Farnesoid?X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4'-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50 =12.2±0.2??M). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. PMID:25982493

  16. A novel class of ion displacement ligands as antagonists of the ?IIb?3 receptor that limit conformational reorganization of the receptor

    PubMed Central

    Jiang, Jian-kang; McCoy, Joshua G.; Shen, Min; LeClair, Christopher A.; Huang, Wenwei; Negri, Ana; Li, Jihong; Blue, Robert; Harrington, Amanda Weil; Naini, Sarasija; David, George; Choi, Won-Seok; Volpi, Elisabetta; Fernandez, Joseph; Babayeva, Mariana; Nedelman, Mark A.; Filizola, Marta; Coller, Barry S.; Thomas, Craig J.

    2014-01-01

    A collection of ?IIb?3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents’ structure-activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development. PMID:24461295

  17. Characterization of a Novel, Linear Radioiodinated Vasopressin Antagonist: An Excellent Radioligand for Vasopressin V1a Receptors

    Microsoft Academic Search

    Claude Barberis; Marie-Noëlle Balestre; Serge Jard; Eliane Tribollet; Yvan Arsenijevic; Jean Jacques Dreifuss; Krysztof Bankowski; Maurice Manning; Walter Y. Chan; Stephan S. Schlosser; Florian Holsboer; Jack Elands

    1995-01-01

    We report on the pharmacological properties of a potent and selective linear vasopressin (AVP) V1a receptor antagonist HO-Phenylacetyl1-D-Tyr(Me)2-Phe3-Gln4-Asn5-Arg6-Pro7-Arg8-NH2 (HO-LVA). Iodinated on the phenolic substituent at position 1, [125I]-HO-LVA displayed the highest affinity for rat liver V1a receptors (8 pM) ever reported. Furthermore, affinities of HO-LVA and I-HO-LVA for V1b, V2 and oxytocin (OT) receptors was 400- to 1,000-fold lower than

  18. The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

    PubMed Central

    Lin, Olivia A.; Karim, Zubair A.; Vemana, Hari Priya; Espinosa, Enma V. P.; Khasawneh, Fadi T.

    2014-01-01

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis. PMID:24466319

  19. Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-? receptor 1 antibody.

    PubMed

    Peng, Li; Oganesyan, Vaheh; Wu, Herren; Dall'Acqua, William F; Damschroder, Melissa M

    2015-01-01

    Anifrolumab (anifrolumab) is an antagonist human monoclonal antibody that targets interferon ? receptor 1 (IFNAR1). Anifrolumab has been developed to treat autoimmune diseases and is currently in clinical trials. To decipher the molecular basis of its mechanism of action, we engaged in multiple epitope mapping approaches to determine how it interacts with IFNAR1 and antagonizes the receptor. We identified the epitope of anifrolumab using enzymatic fragmentation, phage-peptide library panning and mutagenesis approaches. Our studies revealed that anifrolumab recognizes the SD3 subdomain of IFNAR1 with the critical residue R(279). Further, we solved the crystal structure of anifrolumab Fab to a resolution of 2.3 Å. Guided by our epitope mapping studies, we then used in silico protein docking of the anifrolumab Fab crystal structure to IFNAR1 and characterized the corresponding mode of binding. We find that anifrolumab sterically inhibits the binding of IFN ligands to IFNAR1, thus blocking the formation of the ternary IFN/IFNAR1/IFNAR2 signaling complex. This report provides the molecular basis for the mechanism of action of anifrolumab and may provide insights toward designing antibody therapies against IFNAR1. PMID:25606664

  20. Designed abscisic acid analogs as antagonists of PYL-PP2C receptor interactions.

    PubMed

    Takeuchi, Jun; Okamoto, Masanori; Akiyama, Tomonori; Muto, Takuya; Yajima, Shunsuke; Sue, Masayuki; Seo, Mitsunori; Kanno, Yuri; Kamo, Tsunashi; Endo, Akira; Nambara, Eiji; Hirai, Nobuhiro; Ohnishi, Toshiyuki; Cutler, Sean R; Todoroki, Yasushi

    2014-06-01

    The plant stress hormone abscisic acid (ABA) is critical for several abiotic stress responses. ABA signaling is normally repressed by group-A protein phosphatases 2C (PP2Cs), but stress-induced ABA binds Arabidopsis PYR/PYL/RCAR (PYL) receptors, which then bind and inhibit PP2Cs. X-ray structures of several receptor-ABA complexes revealed a tunnel above ABA's 3' ring CH that opens at the PP2C binding interface. Here, ABA analogs with sufficiently long 3' alkyl chains were predicted to traverse this tunnel and block PYL-PP2C interactions. To test this, a series of 3'-alkylsulfanyl ABAs were synthesized with different alkyl chain lengths. Physiological, biochemical and structural analyses revealed that a six-carbon alkyl substitution produced a potent ABA antagonist that was sufficiently active to block multiple stress-induced ABA responses in vivo. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class. PMID:24792952

  1. 5-HT6/7 receptor antagonists facilitate dopamine release in the cochlea via a GABAergic disinhibitory mechanism.

    PubMed

    Doleviczényi, Zoltán; Vizi, E Sylvester; Gacsályi, István; Pallagi, Katalin; Volk, Balázs; Hársing, László G; Halmos, György; Lendvai, Balázs; Zelles, Tibor

    2008-11-01

    In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume superfusion techniques we tested 5-HT(6) and 5-HT(7) receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic conditions using currently available and new 5-HT(6) and 5-HT(7) antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT(7) antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT(6) receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type of receptor. Moreover, the mixed 5-HT(6/7) antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement of an indirect neural mechanism through an inhibitory system. In the presence of the GABA(A) receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic inhibitory tone on dopaminergic nerve endings. The mixed 5-HT(7)/D(4) receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals in the cochlea may have a role in the treatment of sensorineural hearing loss. PMID:18663573

  2. Effects of the non-peptide B 2 receptor antagonist FR173657 in models of visceral and cutaneous inflammation

    Microsoft Academic Search

    T. Griesbacher; F. J. Legat

    2000-01-01

    Objective: The non-peptide B2 receptor antagonist (E)-3-(6-acetamido-3-pyridyl)-N-(N-(2,4-dichloro-3-((2- methyl-8-quinolinyl)oxymethyl)phenyl)-N-methylaminocar- bonylmethyl)acrylamide (FR173657) was compared to the peptide antagonist icatibant in models of visceral and cuta- neous inflammation. Methods: Pancreatitis was induced by caerulein in anaesthe- tized Sprague-Dawley rats. Acute cystitis was induced by intravesical instillation of xylene or i.p. cyclophosphamide injection. Cutaneous inflammation was induced in anaes- thetized guinea-pigs by s.c. injection

  3. In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo.

    PubMed

    Parks, Ashley J; Pollastri, Michael P; Hahn, Mark E; Stanford, Elizabeth A; Novikov, Olga; Franks, Diana G; Haigh, Sarah E; Narasimhan, Supraja; Ashton, Trent D; Hopper, Timothy G; Kozakov, Dmytro; Beglov, Dimitri; Vajda, Sandor; Schlezinger, Jennifer J; Sherr, David H

    2014-11-01

    The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand-induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)- and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC50 3.3 × 10(-7) M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy. PMID:25159092

  4. Ticagrelor: The First Reversibly Binding Oral P2Y12 Receptor Antagonist

    PubMed Central

    Husted, Steen; van Giezen, JJJ

    2009-01-01

    Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS. PMID:19604248

  5. Antidepressant/anxiolytic potential and adverse effect liabilities of melanin-concentrating hormone receptor 1 antagonists in animal models.

    PubMed

    Chaki, Shigeyuki; Shimazaki, Toshiharu; Nishiguchi, Mariko; Funakoshi, Takeo; Iijima, Michihiko; Ito, Akie; Kanuma, Kosuke; Sekiguchi, Yoshinori

    2015-08-01

    Melanin-concentrating hormone receptor 1 (MCH1 receptor) is known to be involved in the control of mood and stress, in addition to the regulation of feeding. Here, we report further evidence that the blockade of the MCH1 receptor exhibits antidepressant and anxiolytic-like effects in a variety of animal models using TASP0382650 and TASP0489838, newly synthesized MCH1 receptor antagonists, with different scaffolds. Both TASP0382650 and TASP0489838 exhibited high affinities for human MCH1 receptor with IC50 values of 7.13 and 3.80nM, respectively. Both compounds showed potent antagonist activities at the MCH1 receptor, as assessed using MCH-increased [(35)S]GTP?S binding to human MCH1 receptor and an MCH-induced [Ca(2+)]i assay in rat MCH1 receptor expressing cells. In contrast, neither TASP0382650 nor TASP0489838 showed an affinity for the MCH2 receptor, another MCH receptor subtype. The oral administration of TASP0382650 or TASP0489838 significantly reduced the immobility time during the forced swimming test in rats, and reduced hyperemotionality induced by an olfactory bulbectomy, both of which are indicative of an antidepressant-like potential. In the olfactory bulbectomy model, the antidepressant effect of TASP0382650 appeared following a single administration, suggesting a faster onset of action, compared with current medications. Moreover, both TASP0382650 and TASP0489838 exhibited anxiolytic effects in several animal models of anxiety. In contrast, both TASP0382650 and TASP0489838 did not affect spontaneous locomotor activity, motor function, spatial memory during the Morris water maze task, or the convulsion threshold to pentylenetetrazole. These findings provide additional evidence that the blockade of the MCH1 receptor exhibits antidepressant- and anxiolytic activities with no adverse effects in experimental animal models. PMID:26044968

  6. Design and Synthesis of Novel Hydrazide-Linked Bifunctional Peptides as ?/? Opioid Receptor Agonists and CCK-1/CCK-2 Receptor Antagonists

    PubMed Central

    Lee, Yeon Sun; Agnes, Richard S.; Badghisi, Hamid; Davis, Peg; Ma, Shou-wu; Lai, Josephine; Porreca, Frank; Hruby, Victor J.

    2006-01-01

    A series of hydrazide-linked bifunctional peptides designed to act as agonists for ? /? opioid receptors and antagonists for CCK-1/CCK-2 receptors was prepared and tested for binding to both opioid and CCK receptors and in functional assays. SAR studies in the CCK region examined the structural requirements for the side chain groups at positions 1?, 2?, and 4? and for the N-terminal protecting group, which are related to interactions not only with CCK, but also with opioid receptors. Most peptide ligands that showed high binding affinities (0.1–10 nM) for both ? and ? opioid receptors generally showed lower binding affinities (micromolar range) at CCK-1 and CCK-2 receptors, but were potent CCK receptor antagonists in the GPI/LMMP assay (up to Ke = 6.5 nM). The results indicate that it is reasonable to design chimeric bifunctional peptide ligands for different G-protein coupled receptors in a single molecule. PMID:16509592

  7. Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3'-substituted deschloroepibatidine analogues. Novel nicotinic antagonists.

    PubMed

    Carroll, F Ivy; Ma, Wei; Yokota, Yasuno; Lee, Jeffrey R; Brieaddy, Lawrence E; Navarro, Hernán A; Damaj, M I; Martin, Billy R

    2005-02-24

    A series of 3'-substituted deschloroepibatidine analogues (3a-g and 4) showed high affinity for alpha4beta2 binding and relatively weak affinity for alpha7 nAChRs. The 3'-ethynyl (3g) and 3'-fluoro (3a) analogues with K(i) values of 0.02 and 0.037 nM, respectively, were the most potent. Even though the alpha4beta2 binding affinity of several of the analogues were equal to that of epibatidine, all of the compounds were weak agonists in the antinociceptive, hypothermia, and spontaneous activity test in mice. In contrast, all of the compounds were functional antagonists of nicotine-induced antinociception. In general, compounds 3a-g and 4 were more potent in the tail-flick assay than the hot-plate test. For example, the 3'-fluoro analogue 3a and the N-methyl-3'-iodo analogue 4 showed AD(50) values of 0.07 and 0.04 microg/kg, respectively, in the tail flick test and only 35 and 0% inhibition at 20 and 10 microg/kg in the hot-plate assay, respectively. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. The high affinity of the N-methyl-3'-iodo analogue 4 combined with its weak agonist and potent antagonist activity suggests that carbon-11 and iodine-123 analogues may be useful as PET and SPECT ligands, respectively, for studying nAChRs in vivo. PMID:15715488

  8. Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2).

    PubMed

    Strunz, Ann Kathrin; Zweemer, Annelien J M; Weiss, Christina; Schepmann, Dirk; Junker, Anna; Heitman, Laura H; Koch, Michael; Wünsch, Bernhard

    2015-07-15

    Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in chronic inflammatory processes such as atherosclerosis, multiple sclerosis and rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamides) was prepared by different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-1,4'-piperidines]) and ?-halobutanamides 11. A key step in the synthesis of spirocyclic piperidines 8 was an Oxa-Pictet-Spengler reaction of ?-phenylethanols 5 with piperidone acetal 6. The substituted ?-hydroxybutanamides 11c-e were prepared by hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the ?-lactones 14c and 14e. Aminolysis of the ?-lactones 14c and 14e with benzylamines provided the ?-hydroxybutanamides 15c-e, which were converted into the bromides 11c-e by an Appel reaction using polymer-bound PPh3. In radioligand binding assays the spirocyclic butanamides 4 did not displace the iodinated radioligand (125)I-CCL2 from the human CCR2. However, in the Ca(2+)-flux assay using human CCR2 strong antagonistic activity of butanamides 4 was detected. Analysis of the IC50-values led to clear relationships between the structure and the inhibition of the Ca(2+)-flux. 4g (4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)-N-[3,5-bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) and 4o (N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamide) represent the most potent CCR2 antagonists with IC50-values of 89 and 17nM, respectively. Micromolar activities were found in the ?-arrestin recruitment assay with murine CCR2, but the structure-activity-relationships detected in the Ca(2+)-flux assay were confirmed. PMID:25766632

  9. Topical Interleukin 1 Receptor Antagonist for Treatment of Dry Eye Disease

    PubMed Central

    Okanobo, Andre; Ferrari, Giulio; Smaga, Leila; Hamrah, Pedram; Jurkunas, Ula; Schaumberg, Debra A.; Dana, Reza

    2014-01-01

    Importance The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy. Objective To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction. Design and Setting Prospective phase 1/2, randomized, double-masked, vehicle-controlled clinical trial. Participants Seventy-five patients with refractory DED. Interventions Participants were randomized to receive treatment with topical anakinra, 2.5% (n=30), anakinra, 5% (n=15), or vehicle (1% carboxymethylcellulose) (n=30) 3 times daily for 12 weeks. Main Outcomes and Measures Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye–related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality. Results Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P=.12 compared with vehicle and P<.001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P=.88 compared with vehicle and P=.33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P=.11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2of 29 patients (7%) treated with vehicle (P=.03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P=.02 and P=.01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms. Conclusions and Relevance Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED. PMID:23599118

  10. 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

  11. RS 23597-190: a potent and selective 5-HT4 receptor antagonist.

    PubMed Central

    Eglen, R. M.; Bley, K.; Bonhaus, D. W.; Clark, R. D.; Hegde, S. S.; Johnson, L. G.; Leung, E.; Wong, E. H.

    1993-01-01

    1. The pharmacological properties of RS 23597-190 (3-(piperdine-1-yl)-propyl-4-amino-5-chloro-2-methoxy benzoate hydrochloride) have been studied in vitro and in vivo. 2. RS 23597-190 competitively antagonized 5-HT4 receptor-mediated relaxations of rat, carbachol precontracted oesophageal muscularis mucosae, (pA2 = 7.8 +/- 0.1; Schild slope = 1.2 +/- 0.2). Affinity estimates (-log KB) at 5-HT4 receptors using either renzapride or SC-53116 as agonists yielded a -log KB value of 8.0 +/- 0.01. In contrast, RS 23597-190 failed to antagonize contractile responses to 5-HT of guinea-pig ileal 5-HT3 receptors, even at concentrations up to 10 microM. 3. Increases in short-circuit current, induced by 5-HT, were studied in guinea-pig ileal mucosal sheets. Concentration-response curves to 5-HT were biphasic, with the high potency phase to 5-HT inhibited by RS 23597-190 and mimicked by 5-methoxytryptamine. The -log KB value for RS 23597-190 at the high potency phase was 7.3 confirming that 5-HT4 receptors mediated the high potency phase. 4. In rat isolated vagus nerve, 5-HT elicited a slow, maintained depolarization at low concentrations and a rapid, transient depolarization at higher concentrations. The high potency, slow depolarizing phase to 5-HT was abolished selectively in the presence of 1 microM RS 23597-190 and the low potency phase was abolished selectively in the presence of 1 microM ondansetron. These data confirm that 5-HT4 and 5-HT3 receptors mediated slow and fast depolarization responses, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8220871

  12. Dihydropyrrolo[2,3-d]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts.

    PubMed

    Watanabe, Manabu; Kasai, Mai; Tomizawa, Hideyuki; Aoki, Masamitsu; Eiho, Kazuo; Isobe, Yoshiaki; Asano, Shigehiro

    2014-11-13

    Toll-like receptors (TLRs) play important roles in the innate immune system. In fact, recognition of endogenous immune complexes containing self-nucleic acids as pathogen- or damage-associated molecular patterns contributes to certain autoimmune diseases, and inhibition of these recognition signals is expected to have therapeutic value. We identified dihydropyrrolo[2,3-d]pyrimidines as novel selective TLR9 antagonists with high aqueous solubility. A structure-activity relationship study of a known TLR9 antagonist led to the promising compound 18, which showed potent TLR9 antagonistic activity, sufficient aqueous solubility for parenteral formulation, and druggable properties. Compound 18 suppressed the production of the proinflammatory cytokine IL-6 in CpG-induced mouse model. It is therefore believed that compound 18 has great potential in the treatment of TLR9-mediated systemic uncontrollable inflammatory response like sepsis. PMID:25408837

  13. Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance.

    PubMed

    Li, Qian

    2012-12-01

    Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance. PMID:23062774

  14. The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test

    PubMed Central

    Costall, Brenda; Naylor, Robert J

    1997-01-01

    The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(?)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse. PMID:9401775

  15. Duration of action of a broad range of selective ?-opioid receptor antagonists is positively correlated with c-Jun N-terminal kinase-1 activation.

    PubMed

    Melief, Erica J; Miyatake, Mayumi; Carroll, F Ivy; Béguin, Cécile; Carlezon, William A; Cohen, Bruce M; Grimwood, Sarah; Mitch, Charles H; Rorick-Kehn, Linda; Chavkin, Charles

    2011-11-01

    The ?-opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective ?-opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel ?-opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: RTI-5989-97 [(3S)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylpropyl]-2-methyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-194 [(3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-241 [(3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)], nor-binaltorphimine (nor-BNI); and (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Seven had short durations of action and did not increase phospho-JNK-ir: RTI-5989-212[(3R)-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylpropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], RTI-5989-240 [(3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], JSPA0658 [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide], JSPA071B [(S)-3-fluoro-4-(4-((2-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide]. PF-4455242 [2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine], PF-4455242 [2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine], FP3FBZ [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide], and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the ?-opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule ?-opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the ?-receptor does not require sustained JNK activation. PMID:21832171

  16. Duration of Action of a Broad Range of Selective ?-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

    PubMed Central

    Melief, Erica J.; Miyatake, Mayumi; Carroll, F. Ivy; Béguin, Cécile; Carlezon, William A.; Cohen, Bruce M.; Grimwood, Sarah; Mitch, Charles H.; Rorick-Kehn, Linda

    2011-01-01

    The ?-opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective ?-opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel ?-opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: RTI-5989-97 [(3S)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylpropyl]-2-methyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-194 [(3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-241 [(3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)], nor-binaltorphimine (nor-BNI); and (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Seven had short durations of action and did not increase phospho-JNK-ir: RTI-5989-212[(3R)-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylpropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], RTI-5989-240 [(3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], JSPA0658 [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide], JSPA071B [(S)-3-fluoro-4-(4-((2-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide]. PF-4455242 [2-methyl-N-((2?-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine], PF-4455242 [2-methyl-N-((2?-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine], FP3FBZ [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide], and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the ?-opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule ?-opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the ?-receptor does not require sustained JNK activation. PMID:21832171

  17. ?-adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling.

    PubMed

    Sharifpanah, Fatemeh; Saliu, Fatjon; Bekhite, Mohamed M; Wartenberg, Maria; Sauer, Heinrich

    2014-11-01

    The ?-adrenoceptor antagonist Propranolol has been successfully used to treat infantile hemangioma. However, its mechanism of action is so far unknown. The hypothesis of this research was that ?-adrenoceptor antagonists may interfere with endothelial cell differentiation of stem cells. Specifically, the effects of the non-specific ?-adrenergic receptor (?-adrenoceptor) antagonist Propranolol, the ?1-adrenoceptor-specific antagonist Atenolol and the ?2-adrenoceptor-specific antagonist ICI118,551 on vasculogenesis of mouse embryonic stem (ES) cells were investigated. All three ?-blockers dose-dependently downregulated formation of capillary structures in ES cell-derived embryoid bodies and decreased the expression of the vascular cell markers CD31 and VE-cadherin. Furthermore, ?-blockers downregulated the expression of fibroblast growth factor-2 (FGF-2), hypoxia inducible factor-1? (HIF-1?), vascular endothelial growth factor 165 (VEGF165), VEGF receptor 2 (VEGF-R2) and phospho VEGF-R2, as well as neuropilin 1 (NRP1) and plexin-B1 which are essential modulators of embryonic angiogenesis with additional roles in vessel remodelling and arteriogenesis. Under conditions of ?-adrenoceptor inhibition, the endogenous generation of nitric oxide (NO) as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) was decreased in embryoid bodies, whereas an increase in NO generation was observed with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Consequently, vasculogenesis of ES cells was restored upon treatment of differentiating ES cells with ?-adrenoceptor antagonists in the presence of NO donor. In summary, our data suggest that ?-blockers impair vasculogenesis of ES cells by interfering with NO generation which could be the explanation for their anti-angiogenic effects in infantile hemangioma. PMID:25130141

  18. Effect of leukotriene receptor antagonists on vascular permeability during endotoxic shock

    SciTech Connect

    Cook, J.A.; Li, E.J.; Spicer, K.M.; Wise, W.C.; Halushka, P.V. (Medical Univ. of South Carolina, Charleston (USA))

    1990-11-01

    Evidence has accumulated that sulfidopeptide leukotrienes are significant pathogenic mediators of certain hematologic and hemodynamic sequelae of endotoxic shock. In the present study, the effects of a selective LTD4/E4 receptor antagonist, LY171883 (LY), or a selective LTD4 receptor antagonist, SKF-104353 (SKF), were assessed on splanchnic and pulmonary localization of 99mTechnetium-labeled human serum albumin (99mTc-HSA) in acute endotoxic shock in the rat. Dynamic gamma camera imaging of heart (H), midabdominal (GI), and lung regions of interest generated time activity curves for baseline and at 5-35 min after Salmonella enteritidis endotoxin (10 mg/kg, i.v.). Slopes of GI/H and lung/H activity (permeability index, GI/H or lung/H X 10(-3)/min) provided indices of intestinal and lung localization. Rats received LY (30 mg/kg, i.v.), LY vehicle (LY Veh), SKF (10 mg/kg), or SKF vehicle (SK Veh) 10 min prior to endotoxin or endotoxin vehicle. In rats receiving the LY Veh and endotoxin (n = 8) or SKF Veh and endotoxin (n = 12), the splanchnic permeability indices to 99mTc-HSA were increased 11.2-fold and 5.1-fold, respectively (P less than 0.05) compared to vehicle control groups not given endotoxin (n = 5). Pulmonary permeability index for 99mTc-HSA was increased (P less than 0.05) to a lesser extent (3.2-fold) by endotoxin compared to vehicle controls. Pretreatment with SKF reduced the mesenteric permeability index to control levels (P less than 0.05) during the 5-35 min time interval post-endotoxin. LY reduced the mesenteric permeability index by 70%. Pulmonary relative permeability to 99mTc-HSA was not affected by LY pretreatment. Both splanchnic and lung relative permeability to the isotope was transient; at 135-225 min post-endotoxin, splanchnic localization of 99mTc-HSA (n = 4) was not significantly different from vehicle controls in these vascular beds.

  19. The cannabinoid CB1 receptor antagonist SR141716A (Rimonabant) enhances the metabolic benefits of long-term treatment with oleoylethanolamide in Zucker rats

    Microsoft Academic Search

    Antonia Serrano; Ignacio del Arco; Francisco Javier Pavón; Manuel Macías; Vidal Perez-Valero; Fernando Rodríguez de Fonseca

    2008-01-01

    Anandamide and oleoylethanolamide (OEA) are lipid mediators that regulate feeding and lipid metabolism. While anandamide, a cannabinoid CB1 receptor agonist, promotes feeding and lipogenesis, oleoylethanolamide, an endogenous agonist of peroxisome proliferator activated receptor alpha (PPAR-?), decreases food intake and activates lipid mobilization and oxidation. The treatment with a cannabinoid CB1 receptor antagonist results in reduction of body weight gain and

  20. Characterization of a novel, linear radioiodinated vasopressin antagonist: an excellent radioligand for vasopressin V1a receptors.

    PubMed

    Barbeis, C; Balestre, M N; Jard, S; Tribollet, E; Arsenijevic, Y; Dreifuss, J J; Bankowski, K; Manning, M; Chan, W Y; Schlosser, S S

    1995-08-01

    We report on the pharmacological properties of a potent and selective linear vasopressin (AVP) V1a receptor antagonist HO-Phenylacetyl1-D-Tyr(Me)2-Phe3-Gln4-Asn5-Arg6-Pro7-Arg8-NH2 (HO-LVA). Iodinated on the phenolic substituent at position 1, [125I]-HO-LVA displayed the highest affinity for rat liver V1a receptors (8 pM) ever reported. Furthermore, affinities of HO-LVA and I-HO-LVA for V1b, V2 and oxytocin (OT) receptors was 400- to 1,000-fold lower than for V1a receptors, rendering it a highly selective ligand. Both HO-LVA and its iodinated derivative are V1 antagonists, they potently inhibited AVP-induced inositol-phosphate accumulation in WRK1 cells, and also, although with a much lower potency, the AVP-induced ACTH release from freshly prepared pituitary cells. Using autoradiography [125I]-HO-LVA appeared to be the first radioligand to successfully identify and localize the presence of V1a receptors in rat liver and blood vessel walls. Moreover, several new brain regions expressing V1a receptors could be identified, in addition to those brain regions that were previously identified with other radiolabelled AVP analogues. PMID:8584113

  1. Effects of bradykinin receptor antagonists on antigen-induced respiratory distress, airway hyperresponsiveness and eosinophilia in guinea-pigs.

    PubMed Central

    Farmer, S. G.; Wilkins, D. E.; Meeker, S. A.; Seeds, E. A.; Page, C. P.

    1992-01-01

    1. We examined effects of bradykinin (BK) receptor antagonists on airway hyperresponsiveness and eosinophilia in sensitized guinea-pigs that had been administered single, as well as repeated (chronic) challenges with inhaled ovalbumin. In addition, the effects of BK antagonists on antigen-induced respiratory distress during the chronic study were noted. 2. At 24 h following single antigen challenge, guinea-pigs exhibited airway hyperresponsiveness to the bronchoconstrictor effect of i.v. histamine, characterized by a left shift in the dose-response curve. In addition, responses to the maximum dose of histamine that could be used were significantly increased in hyperresponsive guinea-pigs. The percentages of bronchoalveolar fluid, eosinophil and neutrophils also increased. 3. A BK B1 receptor antagonist, desArg9-[Leu8]-BK, significantly inhibited airway hyperresponsiveness induced by single antigen challenge. A B2 receptor antagonist, D-Arg-[Hyp3, Thi5,8,D-Phe7]-BK (NPC 349) had a small, but statistically significant inhibitory effect on responsiveness to the highest histamine dose in challenged animals. DesArg9-[Leu8]-BK significantly inhibited the neutrophilia, whereas NPC 349 inhibited infiltration by both cell types. 4. Chronic antigen challenge also caused airway hyperresponsiveness to i.v. acetylcholine (ACh), distinguished by an increase in the slope of the dose-response curve. Thus, the magnitude of the bronchoconstrictor responses to the maximum dose of ACh that could be used was significantly increased. No change in sensitivity to ACh was evident. Marked eosinophilia was also noted in the trachea, bronchi and lung parenchyma. 5. Airway hyperresponsiveness and eosinophilia, induced by chronic antigen challenge, were markedly inhibited by the B2 antagonists, D-Arg-[Hyp3,D-Phe7]-BK (NPC 567) or D-Arg-[Hyp3,Thi5d-Tic7,Tic8]-BK (NPC 16731).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1335332

  2. Involvement of serotonergic system in the effect of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test.

    PubMed

    Fukumoto, Kenichi; Chaki, Shigeyuki

    2015-01-01

    The blockade of metabotropic glutamate 5 (mGlu5) receptor has been reported to exert antidepressant effects in several animal models. We previously reported that both ketamine and an mGlu5 receptor antagonist exerted an effect in a novelty-suppressed feeding (NSF) test, and that the effect of ketamine may be mediated through an ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-dependent increase in serotonergic transmission. However, the involvement of the serotonergic system in the effect of mGlu5 receptor antagonists in the NSF test is not well understood. Therefore, we examined the roles of the serotonergic system in the effect of an mGlu5 receptor antagonist, 6-methyl-2-(phenylethynyl)pyridine hydrochloride (MPEP), in the NSF test in mice. The administration of MPEP significantly shortened the latency to feed, which was not attenuated by the AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). The effect of MPEP was abolished by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effect of MPEP was blocked by a serotonin (5-HT)2A/2C receptor antagonist, ritanserin, but not by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635). These results suggest that the effect of an mGlu5 receptor antagonist may be mediated by the serotonergic system, including the stimulation of the 5-HT2A/2C receptor, in an AMPA receptor-independent manner in the NSF test. PMID:25704019

  3. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies.

    PubMed

    Ojima, Mami; Igata, Hideki; Tanaka, Masayuki; Sakamoto, Hiroki; Kuroita, Takanobu; Kohara, Yasuhisa; Kubo, Keiji; Fuse, Hiromitsu; Imura, Yoshimi; Kusumoto, Keiji; Nagaya, Hideaki

    2011-03-01

    The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of ¹²?I-Sar¹-Ile?-AII to human angiotensin type 1 receptors with an IC?? of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC(50) value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC?? values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC?? values of 242.5, 191.6, >10,000, and >10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC?? value of 9.2 nmol; this effect was resistant to washout (IC?? value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC?? values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC?? value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pD'? value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings. PMID:21123673

  4. Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats.

    PubMed

    Gobert, A; Lejeune, F; Rivet, J M; Audinot, V; Newman-Tancredi, A; Millan, M J

    1995-06-01

    In this study, we used a complementary in vivo electrophysiological and (in individual rats) neurochemical approach to characterize the actions of chemically diverse serotonin (5-HT)1A receptor ligands at central 5-HT1A autoreceptors as compared to dopamine (DA) D2 autoreceptors and presynaptic alpha-2 adrenergic receptors (ARs). The novel, high efficacy, 5-HT1A agonists, WY 48,723 (an arylpiperazine), (+)-flesinoxan (a benzodioxane) and S 14671 and S 14506 (methoxynaphtylpiperazines) mimicked the aminotetralin, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), in inhibiting the firing of dorsal raphe nucleus (DRN) neurons. Similarly, the firing rate of DRN neurons was reduced by the "partial" agonists, MDL 73005EF, BMY 7378, NAN-190, tandospirone and the novel pyrimidinylpiperazine, zalospirone. Furthermore, S 14489, S 15535 and S 15931, novel benzodioxopiperazines, which behave as antagonists at postsynaptic 5-HT1A receptors, inhibited completely DRN firing, whereas the methoxyphenylpiperazine, WAY 100,135, and the aryloxoarylamine, (-)-tertatolol, were ineffective. Indeed, in analogy to spiperone, both WAY 100,135 and (-)-tertatolol behaved as apparently competitive antagonists in that, in their presence, the dose-response curves for inhibition of DRN firing by S 14671, S 14506 or 8-OH-DPAT were shifted in parallel to the right with no loss of maximal effect. In distinction to WAY 100,135 and (-)-tertatolol, a further novel, putative "antagonist," SDZ 216-525 (a benzoisothiazolpiperazine) weakly inhibited the electrical activity of the DRN. With the exception of (-)-tertatolol, which behaved as a weak agonist, a very similar pattern of inhibition of 5-HT turnover was seen in the striatum (innervated by the DRN), the hippocampus and the hypothalamus (DRN and median raphe nucleus) and the spinal cord (nucleus raphe magnus), with the striatum displaying the greatest sensitivity. Drug potency for inhibition of firing and turnover was highly correlated (r = 0.80-0.82) and these actions were significantly correlated to affinity at (hippocampal) 5-HT1A receptors (r = 0.62-0.73). As concerns DA D2 autoreceptors, the agonist action of apomorphine in reducing DA turnover were mimicked only by 8-OH-DPAT, whereas the majority of the other 5-HT1A ligands, in analogy to raclopride, enhanced DA turnover. The facilitation of DA turnover appeared to reflect direct blockade of DA D2 autoreceptors because potency was correlated powerfully to affinity at these D2 sites (r = 0.89).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7791073

  5. Effects of transient receptor potential (TRP) channel agonists and antagonists on slowly adapting type II mechanoreceptors in the rat sinus hair follicle

    Microsoft Academic Search

    Peter M. B. Cahusac

    2009-01-01

    The possible functional role of transient receptor potential (TRP) channels was investigated by testing various TRP agonists and antagonists in an isolated rat sinus hair follicle preparation. Extracellular recordings from slowly adapting type II mechanoreceptor units were made. The antagonist capsazepine depressed spontaneous and mechanically evoked activity, with an IC50 of 82 ?M. In one-third of units, capsazepine caused a

  6. The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V1A receptor antagonists.

    PubMed

    Napier, Susan; Wishart, Grant; Arbuckle, William; Baker, James; Barn, David; Bingham, Matilda; Brown, Angus; Byford, Alan; Claxton, Chris; Craighead, Mark; Buchanan, Kirsteen; Fielding, Lee; Gibson, Lindsay; Goodwin, Richard; Goutcher, Susan; Irving, Nicholas; MacSweeney, Cliona; Milne, Rachel; Mort, Chris; Presland, Jeremy; Sloan, Hazel; Thomson, Fiona; Turnbull, Zara; Young, Trevor

    2011-05-15

    The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists. PMID:21458261

  7. The selective A 2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat

    Microsoft Academic Search

    Alessia Melani; Leonardo Pantoni; Francesca Bordoni; Marco Gianfriddo; Loria Bianchi; Maria Giuliana Vannucchi; Rosalia Bertorelli; Angela Monopoli; Felicita Pedata

    2003-01-01

    Adenosine A2A receptor antagonists have been proved protective in different ischemia models. In this study we verified if the protective effect of the selective A2A antagonist, SCH 58261, could be attributed to the reduction of the excitatory amino acid outflow induced by cerebral focal ischemia. A vertical microdialysis probe was inserted into the striatum of male Wistar rats and, after

  8. 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

  9. 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 17?-estradiol (E2) with a bulky side chain attached to its C-7? position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ER? transactivation activity in a luciferase reporter assay and blocked ER? interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ER?-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ER?, and showed that they could tightly bind to the ER? 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-7? position of E2 can produce ER antagonists with comparable ER affinity as ICI-182,780. PMID:23448346

  10. Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells

    PubMed Central

    1993-01-01

    A previous report showed that the proliferative response of helper T cells to class II major histocompatibility complex (MHC)-restricted antigens can be inhibited by analogues of the antigen, which act as T cell receptor (TCR) antagonists. Here we define and analyze peptide variants that antagonize various functions of class I MHC-restricted cytotoxic T lymphocyte (CTL) clones. Of 64 variants at individual TCR contact sites of the Kb-restricted octamer peptide ovalbumin257-264 (OVAp), a very high proportion (40%) antagonized lysis by three OVAp- specific CTL clones. This effect was highly clone specific, since many antagonists for one T cell clone have differential effects on another. We show that this inhibition of CTL function is not a result of T cell- T cell interaction, precluding veto-like phenomena as a mechanism for antagonism. Moreover, we present evidence for direct interaction between the TCR and antagonist-MHC complexes. In further analysis of the T cell response, we found that serine esterase release and cytokine production are susceptible to TCR antagonism similarly to lysis. Ca2+ flux, an early event in signaling, is also inhibited by antagonists but may be more resistant to the antagonist effect than downstream responses. PMID:8496675

  11. Electrophysiological study of SR 42641, a novel aminopyridazine derivative of GABA: antagonist properties and receptor selectivity of GABAA versus GABAB responses.

    PubMed Central

    Desarmenien, M.; Desaulles, E.; Feltz, P.; Hamann, M.

    1987-01-01

    A new arylamino-pyridazine gamma-aminobutyric acid (GABA) derivative, SR 42641, has been tested for its ability to antagonize the actions of GABA on mammalian sensory neurones. SR 42641 and bicuculline reversibly decreased GABAA-induced depolarizations and currents recorded intracellularly from dorsal root ganglion neurons (DRG). Dose-response curves were shifted to the right in a parallel fashion. KB values (determined under voltage clamp conditions) were respectively 0.12 +/- 0.05 and 0.38 +/- 0.08 microM. Similar values were obtained with current clamp recording conditions. The study of the GABA-induced Cl- current under voltage-clamp conditions did not show any voltage-dependency of the antagonist effect of SR 42641. In nodose ganglion neurones, SR 42641 (0.4-4.5 microM) did not alter the (-)-baclofen-induced shortening of the calcium component of action potentials. At concentrations higher than 10 microM, SR 42641 itself prolonged calcium-dependent action potentials. Patch-clamp recordings from DRG cultured neurones indicated that SR 42641 did not affect the calcium current responsible for sustained calcium entry into cells. We conclude that SR 42641 is a potent competitive GABA antagonist, specific for the GABAA receptor. It does not act at the level of the chloride ionophore. PMID:2435350

  12. A natural androgen receptor antagonist induces cellular senescence in