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1

Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists  

Microsoft Academic Search

Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor

J. Sharkey; I. M. Ritchie; S. P. Butcher; J. S. Kelly

1996-01-01

2

Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice  

Microsoft Academic Search

Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites\\u000a on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine.\\u000a Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17\\u000a mg\\/kg), from saline in a T-maze. Mice rapidly acquired the

B. Geter-Douglass; Jeffrey M. Witkin

1997-01-01

3

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

PubMed Central

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

2014-01-01

4

Discovery of potent competitive antagonists and positive modulators of the P2X2 receptor.  

PubMed

Evaluation and optimization of anthraquinone derivatives related to Reactive Blue 2 at P2X2 receptors yielded the first potent and selective P2X2 receptor antagonists. The compounds were tested for inhibition of ATP (10 ?M) mediated currents in Xenopus oocytes expressing the rat P2X2 receptor. The most potent antagonists were sodium 1-amino-4-[3-(4,6-dichloro[1,3,5]triazine-2-ylamino)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (63, PSB-10211, IC(50) 86 nM) and disodium 1-amino-4-[3-(4,6-dichloro[1,3,5]triazine-2-ylamino)-4-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (57, PSB-1011, IC(50) 79 nM). Compound 57 exhibited a competitive mechanism of action (pA(2) 7.49). It was >100-fold selective versus P2X4, P2X7, and several investigated P2Y receptor subtypes (P2Y(2,4,6,12)); selectivity versus P2X1 and P2X3 receptors was moderate (>5-fold). Compound 57 was >13-fold more potent at the homomeric P2X2 than at the heteromeric P2X2/3 receptor. Several anthraquinone derivatives were found to act as positive modulators of ATP effects at P2X2 receptors, for example, sodium 1-amino-4-(3-phenoxyphenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (51, PSB-10129, EC(50) 489 nM), which led to about a 3-fold increase in the ATP-elicited current. PMID:21207957

Baqi, Younis; Hausmann, Ralf; Rosefort, Christiane; Rettinger, Jürgen; Schmalzing, Günther; Müller, Christa E

2011-02-10

5

Identification of WIN55212-3 as a competitive neutral antagonist of the human cannabinoid CB2 receptor.  

PubMed

1. Several G protein-coupled receptors (GPCRs), including cannabinoid CB(1) and CB(2) receptors, show constitutive activity under heterologous expression. Such a tonic response is generated in the absence of an activating ligand, and can be inhibited by inverse agonists. Neutral antagonists, however, are silent at such receptors, but can reverse both agonist and inverse agonist responses. To date, no neutral antagonist for the CB(2) receptor has been reported. 2. Here, by monitoring receptor-dependent G protein activation, we demonstrate that WIN55212-3 acts as a neutral antagonist at the human CB(2) (hCB(2)) receptor. WIN55212-3 alone, at concentrations competitively antagonized cannabinoid agonist CP-55,940-stimulated responses (pA(2) 6.1). Importantly, the inverse agonism evoked by SR144528 in hCB(2) was dose-dependently reversed by WIN55212-3 (pEC(50) 5.3+/-0.2), indicating true neutral antagonist behavior. 3. Furthermore, WIN55212-3 also antagonized CB(1) receptor signaling in a competitive manner (pA(2) 5.6), but behaved as a partial inverse agonist (pIC(50) 5.5+/-0.1) at the constitutively active human CB(1). 4. Additionally, WIN55212-3 antagonized signaling of the human melatonin MT(1) receptor, with modest activity at the human muscarinic M4 receptor, but it was inactive towards several other GPCRs. 5. These data identify WIN55212-3 as a true neutral hCB(2) receptor antagonist. WIN55212-3 offers a valuable tool for further characterization of ligand activities at the CB(2) receptor and may serve as a lead compound in further efforts to develop more potent and selective neutral CB(2) receptor antagonists. PMID:15852035

Savinainen, Juha R; Kokkola, Tarja; Salo, Outi M H; Poso, Antti; Järvinen, Tomi; Laitinen, Jarmo T

2005-07-01

6

Identification of WIN55212-3 as a competitive neutral antagonist of the human cannabinoid CB2 receptor  

PubMed Central

Several G protein-coupled receptors (GPCRs), including cannabinoid CB1 and CB2 receptors, show constitutive activity under heterologous expression. Such a tonic response is generated in the absence of an activating ligand, and can be inhibited by inverse agonists. Neutral antagonists, however, are silent at such receptors, but can reverse both agonist and inverse agonist responses. To date, no neutral antagonist for the CB2 receptor has been reported. Here, by monitoring receptor-dependent G protein activation, we demonstrate that WIN55212-3 acts as a neutral antagonist at the human CB2 (hCB2) receptor. WIN55212-3 alone, at concentrations ?10?4?M, behaved as a silent ligand exhibiting no agonist or inverse agonist activity. However, WIN55212-3 competitively antagonized cannabinoid agonist CP-55,940-stimulated responses (pA2 6.1). Importantly, the inverse agonism evoked by SR144528 in hCB2 was dose-dependently reversed by WIN55212-3 (pEC50 5.3±0.2), indicating true neutral antagonist behavior. Furthermore, WIN55212-3 also antagonized CB1 receptor signaling in a competitive manner (pA2 5.6), but behaved as a partial inverse agonist (pIC50 5.5±0.1) at the constitutively active human CB1. Additionally, WIN55212-3 antagonized signaling of the human melatonin MT1 receptor, with modest activity at the human muscarinic M4 receptor, but it was inactive towards several other GPCRs. These data identify WIN55212-3 as a true neutral hCB2 receptor antagonist. WIN55212-3 offers a valuable tool for further characterization of ligand activities at the CB2 receptor and may serve as a lead compound in further efforts to develop more potent and selective neutral CB2 receptor antagonists. PMID:15852035

Savinainen, Juha R; Kokkola, Tarja; Salo, Outi M H; Poso, Antti; Järvinen, Tomi; Laitinen, Jarmo T

2005-01-01

7

Non-competitive antagonists of N-methyl-D-aspartate receptors protect cortical and hippocampal cell cultures against glutamate neurotoxicity.  

PubMed

Brief exposure of cortical or hippocampal cell cultures to glutamate (500 microM) resulted in a progressive neuronal necrosis which is maximal 18-24 h later. Pretreatment of the cultures by a phencyclidine derivative: thienylphencyclidine (TCP), or the TCP precursor: GK86, or MK801 protected against glutamate toxicity. Non-competitive antagonists of N-methyl-D-aspartate receptors appear as potent tools for the in vitro protection of neuronal cells against excitatory amino acid toxicity. PMID:2903469

Rondouin, G; Drian, M J; Chicheportiche, R; Kamenka, J M; Privat, A

1988-08-31

8

GABA{sub A} receptor open-state conformation determines non-competitive antagonist binding  

SciTech Connect

The {gamma}-aminobutyric acid (GABA) type A receptor (GABA{sub A}R) is one of the most important targets for insecticide action. The human recombinant {beta}3 homomer is the best available model for this binding site and 4-n-[{sup 3}H]propyl-4'-ethynylbicycloorthobenzoate ([{sup 3}H]EBOB) is the preferred non-competitive antagonist (NCA) radioligand. The uniquely high sensitivity of the {beta}3 homomer relative to the much-less-active but structurally very-similar {beta}1 homomer provides an ideal comparison to elucidate structural and functional features important for NCA binding. The {beta}1 and {beta}3 subunits were compared using chimeragenesis and mutagenesis and various combinations with the {alpha}1 subunit and modulators. Chimera {beta}3/{beta}1 with the {beta}3 subunit extracellular domain and the {beta}1 subunit transmembrane helices retained the high [{sup 3}H]EBOB binding level of the {beta}3 homomer while chimera {beta}1/{beta}3 with the {beta}1 subunit extracellular domain and the {beta}3 subunit transmembrane helices had low binding activity similar to the {beta}1 homomer. GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold by increasing the open probability of the channel. Addition of the {alpha}1 subunit rescued the inactive {beta}1/{beta}3 chimera close to wildtype {alpha}1{beta}1 activity. EBOB binding was significantly altered by mutations {beta}1S15'N and {beta}3N15'S compared with wildtype {beta}1 and {beta}3, respectively. However, the binding activity of {alpha}1{beta}1S15'N was insensitive to GABA and {alpha}1{beta}3N15'S was stimulated much less than wildtype {alpha}1{beta}3 by GABA. The inhibitory effect of etomidate on NCA binding was reduced more than 5-fold by the mutation {beta}3N15'S. Therefore, the NCA binding site is tightly regulated by the open-state conformation that largely determines GABA{sub A} receptor sensitivity. - Graphical Abstract: Display Omitted Research Highlights: > The {beta}1 and {beta}3 subunits were compared by chimeragenesis, mutagenesis and modulators. > Low {beta}1 NCA binding was rescued by replacing its transmembrane helices with those of {beta}3. > GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold. > Mutation at 15' position in TM2 reduced GABA stimulation of NCA binding. > The open-state conformation largely determines GABAA receptor sensitivity to NCAs.

Chen Ligong [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States); Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Xue Ling [Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 (United States); Giacomini, Kathleen M. [Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Casida, John E., E-mail: ectl@berkeley.edu [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States)

2011-02-01

9

Leukotriene receptor antagonist therapy  

PubMed Central

Leukotriene receptor antagonists (LTRA) are a new class of drugs for asthma treatment, available in tablet form. Their unique mechanism of action results in a combination of both bronchodilator and anti-inflammatory effects. While their optimal place in asthma management is still under review, LTRA represent an important advance in asthma pharmacotherapy.???Keywords: leukotriene receptor antagonist; asthma; montelukast; zafirlukast PMID:11085767

Dempsey, O

2000-01-01

10

CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity.  

PubMed

1. The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2. Radioligand binding experiments demonstrated that CGP 37849 potently (Ki 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-((+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nM, and was 4, 5 and 7 fold more potent than the antagonists [+/-)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3. CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4. In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CA1 pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10 microM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. 5. CGP 37849 and CGP 39551 suppressed maximal electroshock-induced seizures in mice with ED50 s of 21 and 4 mg kg'- p.o., respectively. 6. CGP 37849 and CGP 39551 are potent and competitive NMDA receptor antagonists which show significant central effects following oral administration to animals. As such, they may find value as tools to elucidate the roles of NMDA receptors in brain function, and potentially as therapeutic agents for the treatment of neurological disorders such as epilepsy and ischaemic brain damage in man. PMID:1972895

Fagg, G E; Olpe, H R; Pozza, M F; Baud, J; Steinmann, M; Schmutz, M; Portet, C; Baumann, P; Thedinga, K; Bittiger, H

1990-04-01

11

An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site.  

PubMed Central

In view of finding a new gamma-aminobutyric acid (GABA) receptor ligand we synthesized an arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride]. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 microM and a Hill number near 1.0. SR 95103 (1-100 microM) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities. Intraperitoneally administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that St 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable. Images PMID:2984669

Chambon, J P; Feltz, P; Heaulme, M; Restle, S; Schlichter, R; Biziere, K; Wermuth, C G

1985-01-01

12

Gaba receptor insecticide non-competitive antagonists may bind at allosteric modulator sites.  

PubMed

Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and alpha-endosulfan) affect GABA A receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where gamma-HCH (lindane) binds more favorably than beta-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings. PMID:18446586

Law, Richard J; Lightstone, Felice C

2008-05-01

13

Classification of angiotensin receptors in rat isolated uterus, portal vein, and aorta with the novel competitive antagonist sarmesin.  

PubMed

Blockade of in vitro contractile responses to angiotensins II and III by the reversible competitive angiotensin antagonist [Sar1, Tyr(Me)4]ANG II (sarmesin) was investigated in 3 rat smooth muscle tissues. The pA2 values for sarmesin were: rat uterus, 7.46 +/- 0.04 versus ANG II and 7.46 +/- 0.07 versus ANG III; rat aorta, 7.98 +/- 0.07 versus ANG II and 7.67 +/- 0.08 versus ANG III; rat portal vein, 7.75 +/- 0.05 versus ANG II and 7.41 +/- 0.08 versus ANG III. Statistical analysis revealed that the pA2 values in each tissue were not significantly different, suggesting that ANG II and ANG III interact with the same receptors in each tissue. This conclusion was supported by cross-tachyphylaxis studies. Further statistical analysis revealed that pA2 values were not significantly different between tissues, suggesting that there are no readily discernible differences between angiotensin receptors in the 3 smooth muscle preparations investigated. PMID:3227047

Scanlon, M N; Moore, G J

1988-01-01

14

Effects of LY274614, a competitive NMDA receptor antagonist, on the micturition reflex in the urethane-anaesthetized rat.  

PubMed Central

1. The effects of 3 competitive N-methyl-D-aspartate (NMDA) receptor antagonists, LY274614, LY233536 and LY235723, on the micturition reflex and external urethral sphincter EMG activity, were examined either under isovolumetric conditions or during continuous filling cystometry in urethane-anaesthetized (1.2 g kg-1, s.c.) rats. 2. Intravenous administration of LY274614 (3-30 mg kg-1) inhibited in a dose-dependent fashion both bladder and sphincter activity in the intact rats. In addition, the volume threshold for inducing micturition was increased and voided volume was decreased. 3. Intrathecal administration of LY274614 (0.06-30 micrograms) similarly inhibited bladder and sphincter activity during cystometry in intact rats. 4. In chronic spinal cord (T6-T8) transected rats LY274614 (0.1-30 mg kg-1, i.v.) did not alter bladder activity under isovolumetric conditions but decreased the amplitude of micturition contractions and sphincter EMG activity during cystometry at a dose of 10-30 mg kg-1. 5. The inhibitory effects of i.v. administration of LY274614, on bladder and sphincter activity induced by infusion of chemical irritant (0.1% acetic acid) or saline, were similar; except that a slightly larger dose was needed to inhibit sphincter activity during acetic acid infusion. 6. Peak amplitude of micturition contractions recovered to 50% of control 3 h following i.v. (30 mg kg-1) or i.t. (6 micrograms) administration of LY274614. 7. Two other chemically related NMDA antagonists, LY233536 and LY235723 produced similar but less potent effects than LY274614 when given i.v. 8. These data indicate that glutamatergic transmitter mechanisms at the level of the spinal cord are important in modulating bladder activity in the intact animal, but that these mechanisms do not contribute to bladder reflexes in the chronic spinal rat. These mechanisms may, however, contribute to sphincter activity in both intact or chronic spinal rats. PMID:8106110

Yoshiyama, M.; Roppolo, J. R.; Thor, K. B.; de Groat, W. C.

1993-01-01

15

Methadone is a Non-Competitive Antagonist at the ?4?2 and ?3* Nicotinic Acetylcholine Receptors and an Agonist at the ?7 Nicotinic Acetylcholine Receptor.  

PubMed

Nicotine-methadone interactions have been studied in human beings and in various experimental settings regarding addiction, reward and pain. Most methadone maintenance treatment patients are smokers, and methadone administration has been shown to increase cigarette smoking. Previous in vitro studies have shown that methadone is a non-competitive antagonist at rat ?3?4 nicotinic acetylcholine receptors (nAChR) and an agonist at human ?7 nAChRs. In this study, we used cell lines expressing human ?4?2, ?7 and ?3* nAChRs to compare the interactions of methadone at the various human nAChRs under the same experimental conditions. A [(3) H]epibatidine displacement assay was used to determine whether methadone binds to the nicotinic receptors, and (86) Rb(+) efflux and changes in intracellular calcium [Ca(2+) ]i were used to assess changes in the functional activity of the receptors. Methadone displaced [(3) H]epibatidine from nicotinic agonist-binding sites in SH-EP1-h?7 and SH-SY5Y cells, but not in SH-EP1-h?4?2 cells. The Ki values for methadone were 6.3 ?M in SH-EP1-h?7 cells and 19.4 ?M and 1008 ?M in SH-SY5Y cells. Methadone increased [Ca(2+) ]i in all cell lines in a concentration-dependent manner, and in SH-EP1-h?7 cells, the effect was more pronounced than the effect of nicotine treatment. In SH-EP1-h?4?2 cells, the effect of methadone was negligible compared to that of nicotine. Methadone pre-treatment abolished the nicotine-induced response in [Ca(2+) ]i in all cell lines expressing nAChRs. In SH-EP1-h?4?2 and SH-SY5Y cells, methadone had no effect on the (86) Rb(+) efflux, but it antagonized the nicotine-induced (86) Rb(+) ion efflux in a non-competitive manner. These results suggest that methadone is an agonist at human ?7 nAChRs and a non-competitive antagonist at human ?4?2 and ?3* nAChRs. This study adds further support to the previous findings that opioids interact with nAChRs, which may underlie their frequent co-administration in human beings and might be of interest to the field of drug discovery. PMID:25196810

Talka, Reeta; Salminen, Outi; Tuominen, Raimo K

2015-04-01

16

Xanthines as Adenosine Receptor Antagonists  

PubMed Central

The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes. PMID:20859796

Jacobson, Kenneth A.

2013-01-01

17

Pharmacological analysis of calcium antagonist receptors  

SciTech Connect

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.

Reynolds, I.J.

1987-01-01

18

The adenosine receptor antagonist theophylline induces a monoamine-dependent increase of the anticataleptic effects of NMDA receptor antagonists  

Microsoft Academic Search

Previous work revealed that adenosine antagonists as theophylline reversed neuroleptic-induced catalepsy and potentiated anticataleptic effects of dopamine agonists reflecting specific adenosine-dopamine receptor interactions in the central nervous system. We tested whether similar functional interactions exist between adenosine receptors and glutamate receptors of the N-methyl-D-asparte (NMDA) subtype. The present study demonstrates that the anticataleptic effects of the competitive NMDA receptor antagonist

W. Hauber; M. Miinkle

1996-01-01

19

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

SciTech Connect

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.

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

20

Cytokinin receptor antagonists derived from 6-benzylaminopurine.  

PubMed

Recently we reported 6-(2-hydroxy-3-methylbenzylamino)purine (PI-55) as the first molecule to antagonize cytokinin activity at the receptor level. Here we report the synthesis and in vitro biological testing of eleven BAP derivatives substituted in the benzyl ring and in the C2, N7 and N9 positions of the purine moiety. The ability of the compounds to interact with Arabidopsis cytokinin receptors AHK3 and CRE1/AHK4 was tested in bacterial receptor and in live-cell binding assays, and in an Arabidopsis ARR5:GUS (Arabidopsis response regulator 5) reporter gene assay. Cytokinin activity of the compounds was determined in classical cytokinin biotests (tobacco callus, wheat leaf senescence and Amaranthus bioassays). 6-(2,5-Dihydroxybenzylamino)purine (LGR-991) was identified as a cytokinin receptor antagonist. At the molecular level LGR-991 blocks the cytokinin receptor CRE1/AHK4 with the same potency as PI-55. Moreover, LGR-991 acts as a competitive inhibitor of AHK3, and importantly shows reduced agonistic effects in comparison to PI-55 in the ARR5:GUS reporter gene assay and in cytokinin bioassays. LGR-991 causes more rapid germination of Arabidopsis seeds and increases hypocotyl length of dark-grown seedlings, which are characteristics of plants with a reduced cytokinin status. LGR-991 exhibits a structural motive that might lead to preparation of cytokinin antagonists with a broader specificity and reduced agonistic properties. PMID:20189204

Nisler, Jaroslav; Zatloukal, Marek; Popa, Igor; Dolezal, Karel; Strnad, Miroslav; Spíchal, Lukás

2010-05-01

21

Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist  

PubMed Central

Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. Experimental approach: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. Key results: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7±3.9 and 1.0±0.2?nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50=23??mol?kg?1) and monoiodoacetate-induced joint pain (ED50=43??mol?kg?1). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50=28 and 27??mol?kg?1, respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. Conclusions and implications. The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans. PMID:17016515

El-Kouhen, O; Lehto, S G; Pan, J B; Chang, R; Baker, S J; Zhong, C; Hollingsworth, P R; Mikusa, J P; Cronin, E A; Chu, K L; McGaraughty, S P; Uchic, M E; Miller, L N; Rodell, N M; Patel, M; Bhatia, P; Mezler, M; Kolasa, T; Zheng, G Z; Fox, G B; Stewart, A O; Decker, M W; Moreland, R B; Brioni, J D; Honore, P

2006-01-01

22

Chemokine receptor antagonists: overcoming developmental hurdles  

Microsoft Academic Search

Chemokine receptors have a key role in the pathogenesis of autoimmune diseases, inflammation and viral infection. However, with the exception of selective CCR5 antagonists for HIV, the promise of obtaining new therapeutics related to chemokine receptors has not yet been realized. This article highlights some of the recent failures in the clinical trials of chemokine receptor antagonists and explores possible

Richard Horuk

2008-01-01

23

Mutation of an arginine residue in the human glycine receptor transforms ?-alanine and taurine from agonists into competitive antagonists  

Microsoft Academic Search

Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GIyR, substituting Arg271 with either Leu or Gin, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GIyR single-channel conductances to lower

Sundran Rajendra; Joseph W Lynch; Kerrie D Pierce; Chris R French; Peter H Barry; Peter R Schofield

1995-01-01

24

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

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

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

2007-03-01

25

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists  

E-print Network

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

Hubin, Tim

26

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

SciTech Connect

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.

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

27

Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus  

Microsoft Academic Search

Cytokines play key roles in immune responses, inflammation and fibrosis. The balance between levels of cytokines, their receptors and specific inhibitors controls inflammatory reactions in tissues. The pathogenesis of lichen sclerosus is unknown but probably involves cytokine mediators such as interleukin 1 (IL-1) and interleukin 1 receptor antagonist (IL-1ra). The IL-1ra is a competitive inhibitor of IL-1a and IL-1ß, and

Frances E. Clay; Michael J. Cork; Joanna K. Tarlow; Alexandra I. F. Blakemore; Christine I. Harrington; Fiona Lewis; Gordon W. Duff

1994-01-01

28

Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466, a non-competitive AMPA receptor antagonist  

PubMed Central

Given the posited role of enhanced AMPA-mediated synaptic transmission in relapse to drug seeking, we investigated whether the systemic administration of AMPA receptor antagonist GYKI 52466 inhibits cocaine-taking and cocaine-seeking behavior in rats. Rats were trained to self-administer cocaine until stable self-administration was achieved. Effects of GYKI 52466 (1, 3, or 10 mg/kg, i.v.) on cocaine self-administration were assessed. Animals were allowed to reestablish stable cocaine self-administration and were then behaviorally extinguished from drug taking. The effects of GYKI 52466 (3, 10 mg/kg, i.v.) on cocaine-induced reinstatement of drug-seeking behavior were assessed. We found that GYKI 52466 failed to inhibit cocaine-taking and cocaine-seeking in both the self-administration and reinstatement paradigms. We suggest that although AMPA receptors may be involved in cocaine reward and addiction, the AMPA receptor antagonist GYKI 52466 has low therapeutic potential for cocaine addiction treatment. PMID:22206835

Srivastava, Ratika; Xi, Zheng-Xiong; Gardner, Eliot L.

2012-01-01

29

Peptide antagonist of the androgen receptor.  

PubMed

Androgen receptor (AR) is a steroid hormone receptor that is activated by endogenous androgens, mainly testosterone and 5alpha-dihydrotestosterone (5alpha-DHT). AR is also an important drug target, and AR antagonists (antiandrogens) have been widely used for prostate cancer therapy. Antiandrogens currently available on the market are all small molecules that antagonize AR function via binding to the ligand binding domain (LBD). AR peptide antagonist has been proposed as a 'mechanism-based' approach to directly block AR function by interrupting AR-protein interactions from the surface of the receptor. Without targeting the rigid ligand binding pocket within LBD, peptide antagonists allow more flexibility in structure design, and are likely to provide more efficient and complete blockade of AR function as compared to small molecule antagonists. AR interacts with a variety of proteins, and the interaction may be mediated by different functional domains of the receptor. Although varieties of AR-protein interfaces might serve as the target for peptide antagonist, majority of ongoing research is still focusing on peptides that target the LBD, which is mainly due to the abundance of structural information revealed by crystal structures. This review gives an overview of the current research attempts to develop AR peptide antagonists, particularly peptide antagonists that target the LBD and N-terminal domain (NTD). The challenges and opportunities for future discovery and development of peptide antagonists are discussed as well. PMID:20030610

Gao, Wenqing

2010-01-01

30

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists  

PubMed Central

The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to ?-arrestin and stimulated GTP?S binding however CCL17 did not couple to ?-arrestin and only partially stimulated GTP?S binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target. PMID:24534492

Ajram, Laura; Begg, Malcolm; Slack, Robert; Cryan, Jenni; Hall, David; Hodgson, Simon; Ford, Alison; Barnes, Ashley; Swieboda, Dawid; Mousnier, Aurelie; Solari, Roberto

2014-01-01

31

Bradykinin receptors and their antagonists  

Microsoft Academic Search

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

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

1998-01-01

32

Sensitive and rapid behavioral differentiation of N -methyl- d -aspartate receptor antagonists  

Microsoft Academic Search

Behavioral effects of PCP-type noncompetitive antagonists ofN-methyl-d-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (–)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine

Mark J. Ginski; Jeffrey M. Witkin

1994-01-01

33

NMDA Receptor Antagonists for Treatment of Depression.  

PubMed

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

Ates-Alagoz, Zeynep; Adejare, Adeboye

2013-01-01

34

Implementation of a Fluorescence-Based Screening Assay Identifies Histamine H3 Receptor Antagonists Clobenpropit and Iodophenpropit as Subunit-Selective N-Methyl-d-Aspartate Receptor Antagonists  

PubMed Central

N-Methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism. PMID:20197375

Hansen, Kasper B.; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L.; Yuan, Hongjie; Vance, Katie M.; Orr, Anna G.; Kvist, Trine; Ogden, Kevin K.; Le, Phuong; Vellano, Kimberly M.; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T. J.; Snyder, James P.; Bräuner-Osborne, Hans

2010-01-01

35

Antiplatelet therapy: thrombin receptor antagonists  

PubMed Central

Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y12 adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy. PMID:21906120

Tello-Montoliu, Antonio; Tomasello, Salvatore D; Ueno, Masafumi; Angiolillo, Dominick J

2011-01-01

36

Antiplatelet therapy: thrombin receptor antagonists.  

PubMed

Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y(12) adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy. PMID:21906120

Tello-Montoliu, Antonio; Tomasello, Salvatore D; Ueno, Masafumi; Angiolillo, Dominick J

2011-10-01

37

NR2B selective NMDA receptor antagonists.  

PubMed

NR2B antagonists have received considerable attention in recent years. In this class of excitatory amino acid receptor antagonists NR2B antagonists have shown efficacy in neuroprotection, anti-hyperalgesic and anti-Parkinson animal models. Several groups are involved in developing these compounds as therapeutic agents and evaluating newer therapeutic targets for these agents. Until recently benzylpiperidine and phenylpiperidine templates, which were based on the structures of Ifenprodil and Eliprodil, formed the basis of most SAR in this area. A few chemical leads in this class such as CP-101,606, Ro25,6981 and PD0196860 have been identified as possible development leads which have generated significant interest in this area. In addition to the efforts of Pfizer (Parke-Davis), Roche and E.Merck, several other industrial and academic research groups have continued to work in the NR2B area and recently Merck and Roche have reported new chemical leads as NR2B antagonists with significantly different biaryl templates. These new advances have raised hope, for potential success of the NR2B antagonists as new therapeutic agents, for the treatment of several pathophysiological indications. PMID:11945135

Nikam, Sham S; Meltzer, Leonard T

2002-01-01

38

Identification of New Agonists and Antagonists of the Insect Odorant Receptor Co-Receptor Subunit  

PubMed Central

Background Insects detect attractive and aversive chemicals using several families of chemosensory receptors, including the OR family of olfactory receptors, making these receptors appealing targets for the control of insects. Insect ORs are odorant-gated ion channels, comprised of at least one common subunit (the odorant receptor co-receptor subunit, Orco) and at least one variable odorant specificity subunit. Each of the many ORs of an insect species is activated or inhibited by an unique set of odorants that interact with the variable odorant specificity subunits, making the development of OR directed insect control agents complex and laborious. However, several N-,2-substituted triazolothioacetamide compounds (VUAA1, VU0450667 and VU0183254) were recently shown to act directly on the highly conserved Orco subunit, suggesting that broadly active compounds can be developed. We have explored the chemical space around the VUAA1 structure in order to identify new Orco ligands. Principal Findings We screened ORs from several insect species, using heterologous expression in Xenopus oocytes and an electrophysiological assay, with a panel of 22 compounds structurally related to VUAA1. By varying the nitrogen position in the pyridine ring and altering the moieties decorating the phenyl ring, we identified two new agonists and a series of competitive antagonists. Screening smaller compounds, similar to portions of the VUAA1 structure, also yielded competitive antagonists. Importantly, we show that Orco antagonists inhibit odorant activation of ORs from several insect species. Detailed examination of one antagonist demonstrated inhibition to be through a non-competitive mechanism. Conclusions A similar pattern of agonist and antagonist sensitivity displayed by Orco subunits from different species suggests a highly conserved binding site structure. The susceptibility to inhibition of odorant activation by Orco antagonism is conserved across disparate insect species, suggesing the ligand binding site on Orco as a promising target for the development of novel, broadly active insect repellants. PMID:22590607

Chen, Sisi; Luetje, Charles W.

2012-01-01

39

5-Oxo-ETE Receptor Antagonists  

PubMed Central

5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration to the lung during an asthma attack and thereby reduce asthma symptoms. PMID:23581530

Gore, Vivek; Patel, Pranav; Chang, Chih-Tsung; Sivendran, Sashikala; Kang, Namin; Ouedraogo, Yannick P.; Gravel, Sylvie; Powell, William S.; Rokach, Joshua

2013-01-01

40

Phenylthiophenecarboxamide Antagonists of the Olfactory Receptor Co-Receptor Subunit from a Mosquito  

PubMed Central

Insects detect environmental chemicals using chemosensory receptors, such as the ORs, a family of odorant-gated ion channels. Insect ORs are multimeric complexes of unknown stoichiometry, formed by a common subunit (the odorant receptor co-receptor subunit, Orco) and one of many variable subunits that confer odorant specificity. The recent discovery of Orco directed ligands, including both agonists and antagonists, suggests Orco as a promising target for chemical control of insects. In addition to competitively inhibiting OR activation by Orco agonists, several Orco antagonists have been shown to act through a non-competitive mechanism to inhibit OR activation by odorants. We previously identified a series of Orco antagonists, including N-(4-ethylphenyl)-2-thiophenecarboxamide (OX1a, previously referred to as OLC20). Here, we explore the chemical space around the OX1a structure to identify more potent Orco antagonists. Cqui\\Orco+Cqui\\Or21, an OR from Culex quinquefasciatus (the Southern House Mosquito) that responds to 3-methylindole (skatole) and is thought to mediate oviposition behavior, was expressed in Xenopus oocytes and receptor function assayed by two-electrode voltage clamp electrophysiology. 22 structural analogs of OX1a were screened for antagonism of OR activation by an Orco agonist. By varying the moieties decorating the phenyl and thiophene rings, and altering the distance between the rings, we were able to identify antagonists with improved potency. Detailed examination of three of these compounds (N-mesityl-2-thiophenecarboxamide, N-(4-methylbenzyl)-2-thiophenecarboxamide and N-(2-ethylphenyl)-3-(2-thienyl)-2-propenamide) demonstrated competitive inhibition of receptor activation by an Orco agonist and non-competitive inhibition of receptor activation by an odorant. The ability to inhibit OR activation by odorants may be a general property of this class of Orco antagonist, suggesting that odorant mediated behaviors can be manipulated through Orco antagonism. The high conservation of Orco across insect species and previous demonstrations that various Orco ligands are active at ORs derived from several different insect orders suggests that Orco antagonists may have broad applicability. PMID:24358366

Chen, Sisi; Luetje, Charles W.

2013-01-01

41

Renal effects of angiotensin II receptor antagonists.  

PubMed

Among the many roles that angiotensin II plays in the kidney, one of the most important is the direct and indirect regulation of sodium excretion. Angiotensin II is produced within the kidney, where concentrations appear to be far in excess of those detected in plasma. High levels of angiotensin II subtype 1 receptors have been detected on the luminal side of the tubular cells in the proximal convoluted tubule, and these have been implicated in the regulation of sodium excretion. This portion of the nephron is responsible for the reabsorption of 65% of filtered sodium. It is, therefore, reasonable to assume that blockade of these receptors, using non-peptide angiotensin II receptor antagonists, will bring about an increase in renal excretion of sodium. There is, however, the possibility that, if the effect is small, downstream sites will have the capacity to reabsorb the increased sodium delivered to the distal nephron. Studies in hypertensive animal models have established that angiotensin II subtype 1 receptor antagonists stimulate natriuresis. However, the studies that have been performed to date in humans are deficient in that they have been conducted in normotensive subjects. Also, subjects have only been followed up for 6 or 8 h and thus these studies did not examine whether the observed short-term natriuresis was followed by an enhanced reabsorption of sodium. Another study, designed to overcome the deficiencies of previous studies, has investigated the natriuretic effect of telmisartan in hypertensive patients. PMID:11333009

Burgess, E

2001-01-01

42

Fimasartan, a novel angiotensin II receptor antagonist.  

PubMed

Fimasartan (Kanarb®), an angiotensin II receptor antagonist with selectivity for the AT1 receptor subtype, is a pyrimidinone-related heterocyclic compound that was developed by Boryung Pharm. Co., Ltd. Among numerous synthetic derivatives, fimasartan was chosen as a new drug candidate through in vitro and in vivo screening studies. Pharmadynamic-pharmacokinetic properties and safety profiles were determined in a series of nonclinical and clinical studies. Fimasartan is a new angiotensin receptor blocker, and the first new molecular entity acting on cardiovascular system approved by Korean Food and Drug Administration for the treatment of essential hypertension in September 2010. Further development process for combination therapy and overseas registration is currently ongoing. PMID:22864732

Kim, Je Hak; Lee, Joo Han; Paik, Soo Heui; Kim, Ji Han; Chi, Yong Ha

2012-07-01

43

Characterization of a novel non-steroidal glucocorticoid receptor antagonist  

SciTech Connect

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.

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

44

Identification and characterisation of a prototype for a new class of competitive PPAR? antagonists.  

PubMed

Understanding of the physiological role of peroxisome proliferator-activated receptor gamma (PPAR?) offers new opportunities for the treatment of cancers, immune disorders and inflammatory diseases. In contrast to PPAR? agonists, few PPAR? antagonists have been studied, though they do exert immunomodulatory effects. Currently, no therapeutically useful PPAR? antagonist is commercially available. The aim of this study was to identify and kinetically characterise a new competitive PPAR? antagonist for therapeutic use. A PPAR?-dependent transactivation assay was used to kinetically characterise (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB) in kidney, T and monocytic cell lines. Cytotoxic effects were analysed and intracellular accumulation of MTTB was assessed by tandem mass spectrometry (LC-MS/MS). Potential interactions of MTTB with the PPAR? protein were suggested by molecular docking analysis. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), MTTB exhibited competitive antagonism against rosiglitazone in HEK293T and Jurkat T cells, with IC50 values in HEK293T cells of 4.3µM and 1.6µM, using the PPAR? ligand binding domain (PPAR?-LBD) and the full PPAR? protein, respectively. In all cell lines used, however, MTTB showed much higher intracellular accumulation than GW9662. MTTB alone exhibited weak partial agonistic effects and low cytotoxicity. Molecular docking of MTTB with the PPAR?-LBD supported direct interaction with the nuclear receptor. MTTB is a promising prototype for a new class of competitive PPAR? antagonists. It has weak partial agonistic and clear competitive antagonistic characteristics associated with rapid cellular uptake. Compared to commercially available PPAR? modulators, this offers the possibility of dose regulation of PPAR? and immune responses. PMID:25746464

Knape, Tilo; Flesch, Daniel; Kuchler, Laura; Sha, Lisa K; Giegerich, Annika K; Labocha, Sandra; Ferreirós, Nerea; Schmid, Tobias; Wurglics, Mario; Schubert-Zsilavecz, Manfred; Proschak, Eugen; Brüne, Bernhard; Parnham, Michael J; von Knethen, Andreas

2015-05-15

45

Stilbenes as ?-Selective, Non-nitrogenous Opioid Receptor Antagonists  

PubMed Central

The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the ? receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the ? receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid receptor antagonists that are required for activity. PMID:24456556

2015-01-01

46

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

PubMed

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

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

2015-06-01

47

Iontophoresis of Endothelin Receptor Antagonists in Rats and Men  

E-print Network

: The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA ulcers and in some cases to amputation [1]. Therapy of SSc-related ulcers is challenging. Bosentan, a non specific endothelin receptor antagonist (ERA), has been indicated to prevent digital ulcers in patients

Paris-Sud XI, Université de

48

Synthesis of conformationally-constrained stereospecific analogs of glutamic acid as antagonists of metabotropic receptors  

Microsoft Academic Search

Rigid analogs of ACPD have been synthesized to mimick different potential conformations of ACPD in aqueous solution. One of them, (±)-ABHD-I is a competitive antagonist at mGluR1a receptor with a KB value of 300 ?M.

Frédérique Tellier; Francine Acher; Isabelle Brabet; Jean-Philippe Pin; Joël Bockaert; Robert Azerad

1995-01-01

49

Pharmacological characterization of novel A 3 adenosine receptor-selective antagonists  

Microsoft Academic Search

The effects of putative A3 adenosine receptor antagonists of three diverse chemical classes (the flavonoid MRS 1067, the 6-phenyl-1,4-dihydropyridines MRS 1097 and MRS 1191, and the triazoloquinazoline MRS 1220) were characterized in receptor binding and functional assays. MRS1067, MRS 1191 and MRS 1220 were found to be competitive in saturation binding studies using the agonist radioligand [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)adenosine-5?-N-methyluronamide) at cloned

Kenneth A. Jacobson; Kyung-Sun Park; Ji-Long Jiang; Yong-Chul Kim; Mark E. Olah; Gary L. Stiles; Xiao-Duo Ji

1997-01-01

50

Characterization of BU09059: A Novel Potent Selective ?-Receptor Antagonist  

PubMed Central

Kappa-opioid receptor (?) antagonists are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing ?-antagonists has been limited by the pharmacodynamic properties of prototypic ?-selective antagonists; that is, they inhibit receptor signaling for weeks after a single administration. To address this issue, novel trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine derivatives, based on JDTic, were designed using soft-drug principles. The aim was to determine if the phenylpiperidine-based series of ?-antagonists was amenable to incorporation of a potentially metabolically labile group, while retaining good affinity and selectivity for the ?-receptor. Opioid receptor binding affinity and selectivity of three novel compounds (BU09057, BU09058, and BU09059) were tested. BU09059, which most closely resembles JDTic, had nanomolar affinity for the ?-receptor, with 15-fold and 616-fold selectivity over ?- and ?-receptors, respectively. In isolated tissues, BU09059 was a potent and selective ?-antagonist (pA2 8.62) compared with BU09057 (pA2 6.87) and BU09058 (pA2 6.76) which were not ?-selective. In vivo, BU09059 (3 and 10 mg/kg) significantly blocked U50,488-induced antinociception and was as potent as, but shorter acting than, the prototypic selective ?-antagonist norBNI. These data show that a new JDTic analogue, BU09059, retains high affinity and selectivity for the ?-receptor and has a shorter duration of ?-antagonist action in vivo. PMID:24410326

2014-01-01

51

Interleukin-1 receptor antagonist suppresses contact hypersensitivity.  

PubMed

Interleukin-1 receptor antagonist (IL-1ra), a naturally occurring inhibitor of interleukin-1 (IL-1), blocks IL-1 binding to its receptors but has no agonistic activity. IL-1 is thought to play an important role in contact hypersensitivity (CHS), although the effects of exogenously administered IL-1 in CHS have been somewhat controversial. To clarify the role of IL-1 in CHS, we studied the effect of IL-1 receptor blockade using exogenous IL-1ra and evaluated these effects on CHS. We examined the in vivo effects of local administration of recombinant human IL-1ra in the murine CHS model. Local injection of IL-1ra to sensitized BALB/c mice just before challenge with dinitrofluorobenzene resulted in a significant reduction in the intensity of CHS responses, assessed by ear swelling. A dose-response study revealed that maximal inhibition of ear swelling (36% to 43%) was observed after intradermal injection of IL-1ra at doses of 10 to 100 micrograms/ear. This reduction in ear swelling in IL-1ra-injected ears consisted of less inflammatory cell infiltration and decreased edema in the dermis compared with controls. Suppression of CHS was observed when IL-1ra was applied in the 24-h interval preceding challenge with dinitrofluorobenzene, whereas no suppressive effect was observed when IL-1ra was applied 48 h before or after the challenge. Local administration of IL-1ra to naive mice 5 h before sensitization also suppressed CHS responses. However, IL-1ra injection did not suppress phenol-induced inflammation. These results suggest that IL-1ra is an effective inhibitor of both the sensitization and elicitation phases of CHS expression in mice, thus emphasizing the role of IL-1 as an immunologic potentiator of responses associated with CHS. PMID:7665908

Kondo, S; Pastore, S; Fujisawa, H; Shivji, G M; McKenzie, R C; Dinarello, C A; Sauder, D N

1995-09-01

52

Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat  

PubMed Central

Introduction Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM) has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP) injection of cannabinoid CB1 receptor antagonist (AM251) in the presence of alpha-1 adrenergic antagonist (Prazosin) on rat behavior in the EPM. Methods In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg), Prazosin (0.3 mg/kg) and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg). Results Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Discussion Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems. PMID:25337383

Komaki, Alireza; Abdollahzadeh, Fatemeh; Sarihi, Abdolrahman; Shahidi, Siamak; Salehi, Iraj

2014-01-01

53

Pomolic acid, triterpenoid isolated from Licania pittieri, as competitive antagonist of ADP-induced aggregation of human platelets.  

PubMed

Pomolic acid (PA), triterpenoid isolated from Licania pittieri, has previously shown a potent ability to inhibit adenosine diphosphate (ADP)- and epinephrine-induced human platelet aggregation. To investigate whether PA could be an antagonist of ADP-activated receptors of human platelets (P2Y(1) and P2Y(12)), pharmacological studies were conducted to examining its ability to modulate the platelet shape change induced by a selective P2Y(1) receptor agonist MRS2365 and also the nature of its possible interaction with ADP receptors by analyzing the characteristics of log concentration-response curves of ADP constructed in the absence and in the presence of fixed concentrations of PA, using in vitro platelet aggregation assays. PA did not interfere with the activation of P2Y(1) receptor by MRS2365 to induce platelet shape change and displayed a competitive antagonism of ADP-induced platelet aggregation, which most probably involves competition for a single binding site in platelets. The estimated equilibrium dissociate constant (K(b)) of PA as ADP receptor antagonist was 15.4±0.06nM. Together, these findings give indirect evidence for the idea that PA could be a potent competitive antagonist of P2Y(12) receptor, and open the possibility to consider it as new member of the non-nucleotide generation of antiplatelet drugs. PMID:22402243

Alvarado-Castillo, Claudia; Estrada, Omar; Carvajal, Edilmo

2012-04-15

54

Prostanoid receptor antagonists: development strategies and therapeutic applications  

PubMed Central

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

Jones, RL; Giembycz, MA; Woodward, DF

2009-01-01

55

Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo  

PubMed Central

BACKGROUND AND PURPOSE A series of novel non-peptide corticotropin releasing factor type-1 receptor (CRF1) antagonists were found to display varying degrees of insurmountable and non-competitive behaviour in functional in vitro assays. We describe how we attempted to relate this behaviour to ligand receptor-binding kinetics in a quantitative manner and how this resulted in the development and implementation of an efficient pharmacological screening method based on principles described by Motulsky and Mahan. EXPERIMENTAL APPROACH A non-equilibrium binding kinetic assay was developed to determine the receptor binding kinetics of non-peptide CRF1 antagonists. Nonlinear, mixed-effects modelling was used to obtain estimates of the compounds association and dissociation rates. We present an integrated pharmacokinetic–pharmacodynamic (PKPD) approach, whereby the time course of in vivo CRF1 receptor binding of novel compounds can be predicted on the basis of in vitro assays. KEY RESULTS The non-competitive antagonist behaviour appeared to be correlated to the CRF1 receptor off-rate kinetics. The integrated PKPD model suggested that, at least in a qualitative manner, the in vitro assay can be used to triage and select compounds for further in vivo investigations. CONCLUSIONS AND IMPLICATIONS This study provides evidence for a link between ligand offset kinetics and insurmountable/non-competitive antagonism at the CRF1 receptor. The exact molecular pharmacological nature of this association remains to be determined. In addition, we have developed a quantitative framework to study and integrate in vitro and in vivo receptor binding kinetic behaviour of CRF1 receptor antagonists in an efficient manner in a drug discovery setting. PMID:21449919

Ramsey, Simeon J; Attkins, Neil J; Fish, Rebecca; van der Graaf, Piet H

2011-01-01

56

Structure-activity relationships for the competitive angiotensin antagonist [sarcosine,O-methyltyrosine4]angiotensin II (sarmesin).  

PubMed

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(Me)4]ANG II (sarmesin) in which the sarcosine-1, O-methyltyrosine-4, and phenylalanine-8 residues were modified have been synthesized by the solid-phase method. The agonist and antagonist potencies of the 23 peptides synthesized were determined in the rat isolated uterus assay. At position 1, replacement of Sar with Asp, Ala, or Pro gave inactive analogues, and deletion of the N-terminal amino acid produced inactive heptapeptides for all analogues investigated. At position 4, substitution of Tyr with Tyr(Et), D-Tyr, D-Phe, Ile, Thr, or Hyp resulted in inactive analogues, whereas substitution of Phe gave a potent competitive antagonist (pA2 = 7.9), which retained significant agonist activity (22%). For position 8, [Sar1,Tyr(Me)4,Ile8]ANG II and [Sar1,Phe4,Ile8]ANG II were weaker antagonists (pA2 = 6.6 and 6.7, respectively) than [Sar1,Ile8]ANG II (pA2 apparent = 8.1) and, moreover, were reversible competitive antagonists. These findings demonstrate that the structural requirements for receptor blockade by sarmesin are remarkably stringent--modifications at positions 1, 4, and 8 markedly reduce the antagonist activity of this peptide. PMID:3754902

Goghari, M H; Franklin, K J; Moore, G J

1986-06-01

57

Small-molecule antagonists of the orexin receptors.  

PubMed

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

Christopher, John A

2014-01-01

58

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

PubMed

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

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

59

Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors  

PubMed Central

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 [3H]-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

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

60

Non-NMDA receptor antagonist-induced drinking in rat  

NASA Technical Reports Server (NTRS)

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

Xu, Z.; Johnson, A. K.

1998-01-01

61

2-Aminopyridine derivatives as potential ?(2) receptor antagonists.  

PubMed

?(2) Receptor research is receiving increasing interest with regard to the potential of ?(2) proteins as targets for tumor therapy and diagnosis. Nevertheless, knowledge about the ?(2) receptor is far from conclusive. The paucity and modest affinity of known ?(2) antagonists represent one of the limitations to ?(2) receptor research. Previous studies of the high-affinity ?(2) agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine 4 (PB28) suggested that a decrease in lipophilicity might lead to ?(2) ligands devoid of antiproliferative activity (potential ?(2) antagonists). With the aim of producing ?(2) receptor antagonists, we replaced the tetralin nucleus of compound 4 with a 2-aminopyridine moiety. A series of compounds with high affinity for both ? subtypes and with no antiproliferative activity in various cells (mouse HT-22, human SK-N-SH, MCF-7wt, and MCF-7?(1)) were obtained. The effect on Ca(2+) mobilization was investigated for high-affinity compounds 18 and 4, which showed opposite effects. All of the data support the new 2-aminopyridines as high-affinity ? ligands with ?(2) antagonist and ?(1) agonist activity, and, despite the lack of significant ?(2) versus ?(1) selectivity, these novel compounds may be better tools for ? receptor research than the known low-affinity ?(2) antagonists. PMID:22890883

Abate, Carmen; Ferorelli, Savina; Niso, Mauro; Lovicario, Cesarea; Infantino, Vittoria; Convertini, Paolo; Perrone, Roberto; Berardi, Francesco

2012-10-01

62

Allosteric Switching of Agonist/Antagonist Activity by a Single Point Mutation in the Interluekin-1 Receptor Antagonist, IL-1Ra  

PubMed Central

The pleiotropic pro-inflammatory cytokine interleukin (IL)-1? has co-evolved with a competitive inhibitor, IL-1 receptor antagonist (IL-1Ra). IL-1? initiates cell signaling by binding the IL-1 receptor (IL-1R) whereas IL-1Ra acts as an antagonist, blocking receptor signaling. The current paradigm for agonist/antagonist functions for these two proteins is based on the receptor–ligand interaction observed in the crystal structures of the receptor–ligand complexes. While IL-1Ra and IL-1? are structurally homologous, IL-1Ra engages only two of the three extracellular domains of the receptor, whereas IL-1? engages all three. We find that an allosteric functional switch exists within a highly conserved pocket of residues, residues 111–120. This region is maintained across all IL-1 family members and serves as a hydrophobic mini-core for IL-1? folding. A key difference across species is a conserved aromatic residue at position 117 in IL-1?, versus a conserved cysteine in IL-1Ra at the analogous position, 116. We find that the replacement of C116 with a phenylalanine switches the protein from an antagonist to an agonist despite the distant location of C116 relative to receptor interaction sites. These results suggest new ways to develop designer cytokine activity into the ?-trefoil fold and may be of general use in regulation of this large family of signaling proteins. PMID:23499887

Hailey, Kendra L.; Capraro, Dominique T.; Barkho, Sulyman; Jennings, Patricia A.

2013-01-01

63

Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers  

PubMed Central

Background Several peptide hormone receptors were identified that are specifically over-expressed on the cell surface of certain human tumors. For example, high incidence and density of the Y1 subtype of neuropeptide Y (NPY) receptors are found in breast tumors. Recently, we demonstrated that the use of potent radiolabeled somatostatin or bombesin receptor antagonists considerably improved the sensitivity of in vivo imaging when compared to agonists. We report here on the first DOTA-coupled peptidic Y1 receptor affine dimer antagonists. Methods Based on a Y1 affine dimeric peptide scaffold previously reported to competitively antagonize NPY-mediated processes, we have developed new dimeric DOTA-coupled Y1 receptor affine antagonists for scintigraphy and radiotherapy. These dimeric peptides were tested for their specific binding to Y1 expressed in SK-N-MC cells and Y2 expressed in SH-SY5Y as well as for their ability to mediate cAMP production in SK-N-MC cells. Results Introduction of two DOTA moieties at the N-termini of the dimeric NPY analogs as well as the double Asn29 replacement by Dpr(DOTA) or Lys(DOTA) (6 and 10) moiety dramatically reduced binding affinity. However, asymmetric introduction of the DOTA moiety in one segment of the peptidic heterodimer (8 and 11) resulted in suitable antagonists for receptor targeting with high binding affinity for Y1. All compounds were devoid of Y2 binding affinity. Conclusions The design and the in vitro characterization of the first DOTA-coupled dimeric NPY receptor antagonist with high affinity and selectivity for Y1 over Y2 are described. This compound may be an excellent candidate for the imaging of Y1-positive tumors and their treatment. PMID:22214201

2011-01-01

64

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

PubMed Central

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

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

65

Inhibition of acetylcholinesterase modulates NMDA receptor antagonist mediated alterations in the developing brain.  

PubMed

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

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

66

Disubstituted piperidines as potent Orexin (hypocretin) receptor antagonists  

PubMed Central

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

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

67

BEHAVIORAL NEUROSCIENCE Orexin / hypocretin 1 receptor antagonist reduces heroin  

E-print Network

BEHAVIORAL NEUROSCIENCE Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking Rachel J. Smith and Gary Aston-Jones Department of Neurosciences, Medical experiments, we examined the involvement of orexin in heroin reinforcement and relapse by administering

Aston-Jones, Gary

68

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

PubMed Central

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

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

69

ADP receptor antagonists as antiplatelet therapeutics.  

PubMed

With the cloning of the P2Y12 receptor, the molecular basis for ADP-induced platelet aggregation is seemingly complete. Two platelet-bound ADP receptors, P2Y1 and P2Y12, operate through unique pathways to induce and sustain platelet aggregation via the glycoprotein (GP)IIb-IIIa integrin. P2Y1 operates via a glycoprotein q (Gq) pathway, activates phospholipase C, induces platelet shape change and is responsible for intracellular calcium mobilisation. P2Y12 inhibits adenylyl cyclase through a glycoprotein i (Gi)-dependent pathway, and is the target of the clinically used thienopyridines, ticlopidine (Ticlid, F. Hoffman-La Roche) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Synthelabo). In addition, the receptor is targeted by the ADP analogue AR-C66096, which is currently in Phase IIb clinical trials, as well as other non-nucleoside-based preclinical leads. PMID:14610915

Bauer, Shawn M

2003-05-01

70

Possible therapeutic application of GABAB receptor agonists and antagonists.  

PubMed

After their discovery within the mammalian periphery in 1981, gamma-aminobutyric acid-B (GABAB) receptors have been characterized also in the central nervous system (CNS). The highest concentrations of GABAB binding sites appear to be in the cerebellum, frontal cortex, and thalamic nuclei, where they are located on pre- and postsynaptic neurons. On activation, the primary effects appear to be membrane hyperpolarization, suppression of transmitter release, and changes in the levels of cyclic nucleotides. GABAB receptors have been implicated in a variety of neurological phenomena and, as a consequence, receptor agonists and antagonists may well have therapeutic potential. This article is an introduction to GABAB receptor pharmacology and reviews the future of the receptor ligands. Particular attention is given to the role of spinal cord GABAB receptors in chronic pain. PMID:8665542

Malcangio, M; Bowery, N G

1995-08-01

71

Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs.  

PubMed

Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) were identified in the mid 90s as a novel peptidergic system structurally related to opioids. A growing body of preclinical evidence suggests that blockade of NOP receptors evokes antidepressant-like actions. These have been explored using a range of compounds (peptide and non peptide antagonists), across different species (rat and mouse) and assays (behavioral despair and chronic mild stress) suggesting a robust and consistent antidepressant-like effect. Moreover, rats and mice knockout for the NOP receptor gene display an antidepressant-like phenotype in behavioral despair assays. Electrophysiological, immunohistochemical and neurochemical studies point to an important role played by monoaminergic systems, particularly 5-HTergic, in mediating the antidepressant-like properties of NOP antagonists. However other putative mechanisms of action, including modulation of the CRF system, circadian rhythm and a possible neuroendocrine-immune control might be involved. A close relationship between the N/OFQ-NOP receptor system and stress responses is well described in the literature. Stressful situations also alter endocrine, behavioral and neurochemical parameters in rats and chronic administration of a NOP antagonist restored these alterations. Interestingly, clinical findings showed that plasma N/OFQ levels were significantly altered in major and post-partum depression, and bipolar disease patients. Collectively, data in the literature support the notion that blockade of NOP receptor signaling could be a novel and interesting strategy for the development of innovative antidepressants. PMID:23711793

Gavioli, Elaine Cristina; Calo', Girolamo

2013-10-01

72

Protease-activated receptor-1 antagonists: focus on SCH 530348.  

PubMed

Currently available antiplatelet agents have shown improved short- and long-term clinical outcomes but are associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of protease-activated receptor-1 for thrombin represents a potential novel strategy to reduce ischemic events without increasing the risk of bleeding. Two protease-activated receptor-1 antagonists are currently being evaluated in clinical trials: SCH 530348 and E5555. Results of phase II trials have shown that SCH 530348, when added to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. Two large-scale phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This review provides an outline of the current status of understanding on platelet thrombin-receptor antagonist SCH 530348, focusing on its pharmacologic properties and clinical development. PMID:21248619

Sugunaraj, Jaya Prakash; Mehta, Vimal; Kalra, Ankur; Sukhija, Rishi; Palaniswamy, Chandrasekar

2012-11-01

73

NMDA Receptors Mediate Synaptic Competition in Culture  

Microsoft Academic Search

BackgroundActivity 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

Kevin She; Ann Marie Craig; Thomas A. Reh

2011-01-01

74

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

Microsoft Academic Search

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

Per-Göran Gillberg; Staffan Sundquist; Lisbeth Nilvebrant

1998-01-01

75

Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist  

NASA Astrophysics Data System (ADS)

The glucagon analog [l-N?-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

1982-02-01

76

A Highly Selective Cc Chemokine Receptor (Ccr)8 Antagonist Encoded by the Poxvirus Molluscum Contagiosum  

PubMed Central

The MC148 CC chemokine from the human poxvirus molluscum contagiosum (MCV) was probed in parallel with viral macrophage inflammatory protein (vMIP)-II encoded by human herpesvirus 8 (HHV8) in 16 classified human chemokine receptors. In competition binding using radiolabeled endogenous chemokines as well as radiolabeled MC148, MC148 bound with high affinity only to CCR8. In calcium mobilization assays, MC148 had no effect on its own on any of the chemokine receptors, but in a dose-dependent manner blocked the stimulatory effect of the endogenous I-309 chemokine on CCR8 without affecting chemokine-induced signaling of any other receptor. In contrast, vMIP-II acted as an antagonist on 10 of the 16 chemokine receptors, covering all four classes: XCR, CCR, CXCR, and CX3CR. In chemotaxis assays, MC148 specifically blocked the I-309–induced response but, for example, not stromal cell–derived factor 1?, monocyte chemoattractant protein 1, or interleukin 8–induced chemotaxis. We thus concluded that the two viruses choose two different ways to block the chemokine system: HHV8 encodes the broad-spectrum chemokine antagonist vMIP-II, whereas MCV encodes a highly selective CCR8 antagonist, MC148, conceivably to interfere with monocyte invasion and dendritic cell function. Because of its pharmacological selectivity, the MC148 protein could be a useful tool in the delineation of the role played by CCR8 and its endogenous ligand, I-309. PMID:10620615

Lüttichau, Hans R.; Stine, Johnny; Boesen, Thomas P.; Johnsen, Anders H.; Chantry, David; Gerstoft, Jan; Schwartz, Thue W.

2000-01-01

77

Small molecule ghrelin receptor inverse agonists and antagonists.  

PubMed

Ghrelin is an endogenous peptide hormone secreted primarily by the stomach and is involved in a number of physiological processes including growth hormone secretion, food intake, as well as energy and glucose homeostasis. The physiological actions of ghrelin are mediated through the growth hormone secretagogue receptor 1a (ghrelin receptor), a peptidic G-protein-coupled receptor. This target has attracted much interest, as agents that block ghrelin's actions on its receptor are anticipated to be pharmaceutical interventions for a number of diseases. This review provides an overview of ghrelin biology with a focus on metabolic diseases and summarizes recent medicinal chemistry programs aimed at delivering small molecule ghrelin receptor antagonists and inverse agonists to the clinic. PMID:25036503

Cameron, Kimberly O; Bhattacharya, Samit K; Loomis, A Katrina

2014-11-13

78

Identification of a Novel “Almost Neutral” Mu Opioid Receptor Antagonist in CHO Cells Expressing the Cloned Human Mu Opioid Receptor  

PubMed Central

The basal (constitutive) activity of G protein-coupled receptors allows for the measurement of inverse agonist activity. Some competitive antagonists turn into inverse agonists under conditions where receptors are constitutively active. In contrast, neutral antagonists have no inverse agonist activity, and they block both agonist and inverse agonist activity. The mu opioid receptor (MOR) demonstrates detectable constitutive activity only after a state of dependence is produced by chronic treatment with a MOR agonist. We therefore sought to identify novel MOR inverse agonists, and novel neutral MOR antagonists in both untreated and agonist-treated MOR cells. CHO cells expressing the cloned human mu receptor (hMOR-CHO cells) were incubated for 20 hr with medium (control) or 10 ?M (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK-treatment generates a high degree of basal signaling and enhances the ability to detect inverse agonists. [35S]-GTP-?-S assays were conducted using established methods. We screened 21 MOR “antagonists” using membranes prepared from HERK-treated hMOR-CHO cells. All antagonists, including CTAP and 6?-naltrexol, were inverse agonists. However, LTC-2 7 4 ( (-)-3-cyclopropylmethyl-2,3,4,4a?,5,6,7,7a?-octahydro-1H-benzofuro[3,2-e]isoquinolin-9-ol)) showed the lowest efficacy as an inverse agonist, and, at concentrations less than 5 nM, had minimal effects on basal [35S]-GTP-?-S binding. Other efforts in this study identified KC-2-009 ((+)-3-((1R,5S)-2-((Z)-3-Phenylallyl)-2-azabicyclo[3.3.1]nonan-5-yl)phenol hydrochloride) as an inverse agonist at untreated MOR cells. In HERK-treated cells, KC-2-009 had the highest efficacy as an inverse agonist. In summary, we identified a novel and selective MOR inverse agonist (KC-2-009), and a novel MOR antagonist (LTC-274) that shows the least inverse agonist activity among 21 MOR antagonists. LTC-274 is a promising lead compound for developing a true MOR neutral antagonist. PMID:19953652

Sally, Elliott J.; Xu, Heng; Dersch, Christina M.; Hsin, Ling-Wei; Chang, Li-Te; Prisinzano, Thomas E.; Simpson, Denise S.; Giuvelis, Denise; Rice, Kenner C.; Jacobson, Arthur E.; Cheng, Kejun; Bilsky, Edward J.; Rothman, Richard B.

2009-01-01

79

The N-methyl- d-aspartate (NMDA) receptor glycine site antagonist ACEA 1021 does not produce pathological changes in rat brain  

Microsoft Academic Search

ACEA 1021 is a potent, selective N-methyl-d-aspartate (NMDA) receptor glycine site antagonist under clinical evaluation as a neuroprotectant for stroke and head trauma. The potential of ACEA 1021 to produce morphologic changes in cerebrocortical neurons of the rat was assessed since it is known that noncompetitive (e.g., MK-801) and competitive (e.g., CGS 19755) NMDA receptor antagonists produce neuronal vacuolization and

Jon E. Hawkinson; Kirk R. Huber; Pritam S. Sahota; Helen Han Hsu; Eckard Weber; M. J. Whitehouse

1997-01-01

80

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse  

PubMed Central

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

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

2014-01-01

81

Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine.  

PubMed

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

Funder, John W

2013-01-01

82

Characterization of VIP receptor-effector system antagonists in rat and mouse peritoneal macrophages.  

PubMed

In the present study we show that the synthetic peptides [4-Cl-D-Phe6,Leu17]VIP and the growth hormone releasing factor (GRF) analog [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 inhibit in a competitive manner the specific [125I]VIP binding to both rat and mouse peritoneal macrophages. In rat peritoneal macrophages, the order of potency of the different peptides, as expressed by the IC50 values was: VIP (IC50 = 1.90 +/- 0.16 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 125.8 +/- 13.2 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 354.8 +/- 21.2 nM). In mouse peritoneal macrophages a similar pattern of potency was observed: VIP (IC50 = 1.58 +/- 0.12 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 110.8 +/- 10.7 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 251 +/- 19.2 nM). The behavior as VIP receptor antagonists of both [4-Cl-D-Phe6,Leu17]VIP and [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 in rat and mouse peritoneal macrophages was confirmed by: (a) the shift to the right of VIP dose-stimulated cyclic AMP production curves in the presence of the two antagonists; (b) the agreement between the order of efficacy of the two peptides in competition experiments with the corresponding inhibition of cyclic AMP production; (c) the inefficiency of the two antagonists on the stimulation of cyclic AMP production by the beta-adrenoceptor agonist isoproterenol, which indicates the specificity of the interaction; (d) the synergic effect of VIP on isoproterenol-stimulated cyclic AMP production was completely abolished by [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2, suggesting that both antagonists acted via specific VIP receptors. Moreover, propranolol, a beta-adrenoceptor antagonist, did not affect the VIP-stimulated cyclic AMP production and the antagonist role of [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2; (e) in cross-linking experiments, the intensity of the labeling of the [125I]VIP/receptor complexes was significantly lower with the antagonists than in the control experimental situation in both mouse and rat peritoneal macrophage membranes. PMID:9085051

Pozo, D; Montilla, M L; Guerrero, J M; Calvo, J R

1997-03-01

83

Bronchoprotection with a Leukotriene Receptor Antagonist in Asthmatic Preschool Children  

Microsoft Academic Search

We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double- blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5 mg\\/d for 2 d on the bron- choconstriction induced by hyperventilation of cold, dry air in 13 asthmatic children 3

HANS BISGAARD; KIM G. NIELSEN

2000-01-01

84

A functional comparison of the antagonists bicuculline and picrotoxin at recombinant GABAA receptors.  

PubMed

Allosteric modulation of GABAA receptor function by a number of ligands has been shown to be dependent on the subunit composition of the receptor complex. In this respect, modulation of GABAA receptors by the antagonists bicuculline and picrotoxin was examined in Xenopus laevis oocytes expressing recombinant GABAA receptors composed of combinations of murine alpha 1, beta 1, gamma 2S and gamma 2L subunits. Bicuculline and picrotoxin reduced GABA-activated responses mediated by GABAA receptors composed of alpha 1 beta 1, alpha 1 beta 1 gamma 2S and alpha 1 beta 1 gamma 2L subunits in a dose-dependent manner. GABA equilibrium concentration-response curves for each receptor construct were shifted to the right by increasing concentrations of bicuculline in a competitive manner, whereas picrotoxin induced a slight lateral shift as well as a depression of the maximum response consistent with a mixed/non-competitive inhibitory mechanism. GABA concentration-response curves in the absence and presence of bicuculline were subjected to Schild analysis, which revealed similar pKB values of approximately 5.9 for alpha 1 beta 1, alpha 1 beta 1 gamma 2S and alpha 1 beta 1 gamma 2L receptor constructs. Concentration inhibition curves were used to estimate IC50 for picrotoxin were relatively unaffected by the GABAA receptor isoforms used in this study, and in particular, by the absence of the gamma 2 subunit in the alpha 1 beta 1 GABAA receptor complex. The similarity of the pKBs reported in this study to those previously reported using native neuronal preparations, which are likely to represent heterogeneous GABAA receptor populations, further indicates the lack of dependence on receptor subunit composition for the inhibitory action of bicuculline. PMID:9014144

Krishek, B J; Moss, S J; Smart, T G

1996-01-01

85

Novel anti-platelet agents: focus on thrombin receptor antagonists.  

PubMed

Platelets are the key in the pathogenesis of atherothrombotic disease such as acute coronary syndromes, stroke, and peripheral arterial disease. Current anti-platelet treatments are mainly based on inhibition of two important pathways of platelet activation: thromboxane A2 (TXA2) mediated (aspirin) and adenosine diphosphate (ADP)-P2Y12 receptor mediated (clopidogrel, prasugrel, and ticagrelor). Despite the dual anti-platelet therapy with aspirin and P2Y12 inhibitors have reduced ischemic events in patients with acute coronary syndromes (ACS), the rate of recurrent ischemic complication after ACS remains high. Combination of multiple anti-platelet agents is also associated with increased risk of bleeding. Thrombin is a potent platelet agonist and the increase of its activity has been reported in patients with ACS. Platelet effects of thrombin are mediated by protease-activated receptors (PAR), and PAR-1 is the most important receptor in human platelets. Two PAR-1 antagonists, vorapaxar and atopaxar, have undergone clinical investigation. In this review, we will describe the pharmacology of PAR-1 antagonists and will review and discuss results of randomized clinical trials with PAR-1 antagonists. PMID:23435863

de Souza Brito, Flavio; Tricoci, Pierluigi

2013-06-01

86

At last, a truly selective EP2 receptor antagonist  

PubMed Central

Ever since the discovery of prostaglandin E2 (PGE2), this lipid mediator has been the focus of intense research. The diverse biological effects of PGE2 are due, at least in part, to the existence of four distinct receptors (EP1–4). This can complicate the analysis of the biological effects produced by PGE2. While there are currently selective pharmacological tools to explore the roles of the EP1,3,4 receptors in cellular and tissue responses, analysis of EP2 receptor-induced responses has been hampered by the lack of a selective EP2 receptor antagonist. The recent publication in this journal by af Forselles et al. suggests that such a tool compound is now available. In their manuscript, the authors describe a series of experiments that show PF-04418948 to be a potent and selective EP2 receptor antagonist. The discovery of this tool compound will interest many scientists and through collaborations with Pfizer they may have access to PF-04418948 to facilitate further investigation of the biology of this fascinating lipid mediator. LINKED ARTICLE This article is a commentary on af Forselles et al., pp. 1847–1856 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01495.x PMID:21595650

Birrell, Mark A; Nials, Anthony T

2011-01-01

87

IL-36 receptor antagonist with special emphasis on IL-38.  

PubMed

IL-36 is another family member of IL-1 and induces the production of proinflammatory cytokines and activates MAPK and NFkB pathways. IL-36 is a common mediator of innate and adaptive immune response and is inhibited by IL-36 receptor antagonist (RA). IL-36RA acts on IL-36 receptor ligand which exerts proinflammatory effect in vivo and in vitro. IL-38 binds to IL-36 receptor as does IL-36RA and has similar biological effects on immune cells. IL-38 is also a member of IL-1 cytokine and shares some characteristics of IL-1RA, binding the same IL-1 receptor type I. IL-38 plays a role in the pathogenesis of inflammatory diseases, exerting protective effect in some autoimmune diseases. Both IL-38 and IL-36RA have an anti-inflammatory biological effect, however in some cases have contrary effects. PMID:23527706

Shaik, Y; Sabatino, G; Maccauro, G; Varvara, G; Murmura, G; Saggini, A; Rosati, M; Conti, F; Cianchetti, E; Caraffa, A; Antinolfi, P; Pandolfi, F; Potalivo, G; Galzio, R; Conti, P; Theoharides, T C

2013-01-01

88

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor.  

PubMed

We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies. PMID:12167464

Anthes, John C; Gilchrest, Helen; Richard, Christian; Eckel, Stephen; Hesk, Dave; West, Robert E; Williams, Shirley M; Greenfeder, Scott; Billah, Motasim; Kreutner, William; Egan, Robert E

2002-08-01

89

Characterization of a Sphingosine 1-Phosphate Receptor Antagonist ProdrugS?  

PubMed Central

Sphingosine 1-phosphate (S1P) is a phospholipid that binds to a set of G protein-coupled receptors (S1P1–S1P5) to initiate an array of signaling cascades that affect cell survival, differentiation, proliferation, and migration. On a larger physiological scale, the effects of S1P on immune cell trafficking, vascular barrier integrity, angiogenesis, and heart rate have also been observed. An impetus for the characterization of S1P-initiated signaling effects came with the discovery that FTY720 [fingolimod; 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] modulates the immune system by acting as an agonist at S1P1. In the course of structure-activity relationship studies to better understand the functional chemical space around FTY720, we discovered conformationally constrained FTY720 analogs that behave as S1P receptor type-selective antagonists. Here, we present a pharmacological profile of a lead S1P1/3 antagonist prodrug, 1-(hydroxymethyl)-3-(3-octylphenyl)cyclobutane (VPC03090). VPC03090 is phosphorylated by sphingosine kinase 2 to form the competitive antagonist species 3-(3-octylphenyl)-1-(phosphonooxymethyl)cyclobutane (VPC03090-P) as observed in guanosine 5?-O-(3-[35S]thio)triphosphate binding assays, with effects on downstream S1P receptor signaling confirmed by Western blot and calcium mobilization assays. Oral dosing of VPC03090 results in an approximate 1:1 phosphorylated/alcohol species ratio with a half-life of 30 h in mice. Because aberrant S1P signaling has been implicated in carcinogenesis, we applied VPC03090 in an immunocompetent mouse mammary cancer model to assess its antineoplastic potential. Treatment with VPC03090 significantly inhibited the growth of 4T1 primary tumors in mice. This result calls to attention the value of S1P receptor antagonists as not only research tools but also potential therapeutic agents. PMID:21632869

Kennedy, Perry C.; Zhu, Ran; Huang, Tao; Tomsig, Jose L.; Mathews, Thomas P.; David, Marion; Peyruchaud, Olivier; Macdonald, Timothy L.

2011-01-01

90

Preclinical anxiolytic profiles of 7189 and 8319, novel non-competitive NMDA antagonists  

SciTech Connect

Antagonists at excitatory amino acid receptors, especially the N-methyl-d-aspartate (NMDA) subtype, have been shown to possess anticonvulsant and anxiolytic properties. Two closely related benzeneethanamines, are potential novel anxiolytic agents which bind with high affinity to the NMDA receptor at the non-competitive site and are relatively non-toxic (LD50's-160 mg/kg, ip). 7189 and 8319 showed anxiolytic effects in schedule controlled conflict assays as well as in the social interaction (SI) and elevated plus maze (EPM) procedures in rats. Following intraperitoneal administration of 7189 at 20 to 60 mg/kg, conflict responding was increased from 2- to 7-fold in the modified Cook and Davidson and Geller conflict paradigms. 8319, at 2.5 to 5 mg/kg, produced a two fold increase in conflict responding. In the non-schedule controlled procedures, 7189 at 20 mg/kg increased SI time by 23% while in the EPM at 10 to 20 mg/kg, open arm exploration time increased by 41 to 77%. Likewise, 8319 at 2.5 and 5 mg/kg increased open arm exploration and SI time by 50 and 37%, respectively. In summary, 7189 and 8319 were efficacious in four behavioral procedures predictive of potential anxiolytic agents. Although these compounds have not been submitted for clinical evaluation, they may represent a new class of beneficial compounds for the treatment of anxiety.

Dunn, R.W.; Corbett, R.; Martin, L.L.; Payack, J.F.; Laws-Ricker, L.; Wilmot, C.A.; Rush, D.K.; Cornfeldt, M.L.; Fielding, S. (Hoechst-Roussel Pharmaceuticals, Inc. Somerville, NJ (USA))

1990-01-01

91

Interaction of fenoterol stereoisomers with ?2-adrenoceptor-G s? fusion proteins: antagonist and agonist competition binding.  

PubMed

The specific interaction between G-protein-coupled receptors and ligand is the starting point for downstream signaling. Fenoterol stereoisomers were successfully used to probe ligand-specific activation (functional selectivity) of the ?2-adrenoceptor (?2AR) (Reinartz et al. 2015). In the present study, we extended the pharmacological profile of fenoterol stereoisomers using ?2AR-Gs? fusion proteins in agonist and antagonist competition binding assays. Dissociations between binding affinities and effector potencies were found for (R,S')- and (S,S')-isomers of 4'-methoxy-1-naphthyl-fenoterol. Our data corroborate former studies on the importance of the aminoalkyl moiety of fenoterol derivatives for functional selectivity. PMID:25637582

Reinartz, Michael T; Kälble, Solveig; Wainer, Irving W; Seifert, Roland

2015-05-01

92

Comparative antihypertensive effects of angiotensin II receptor antagonists.  

PubMed

Blockade of the renin-angiotensin system is recognized as an effective approach for the treatment of hypertension and congestive heart failure. It is possible to antagonize the effects of angiotensin II (AngII) by blocking its receptors, using nonpeptide receptor antagonists. Six angiotensin receptor blockers (ARB) have been approved for the treatment of hypertension: losartan, valsartan, irbesartan, candesartan, telmisartan, and eprosartan. These new drugs are highly selective for the AT1 receptor subtype and induce dose-dependent inhibition of the BP response to exogenous AngII. Numerous double-blind, placebo-controlled studies have demonstrated that ARB are efficacious for treating mild, moderate, and severe hypertension. When compared with other classes of antihypertensive agents, ARB are as effective as angiotensin-converting enzyme inhibitors, calcium antagonists, thiazide diuretics, and beta-blockers. One advantage of ARB as a class is their excellent tolerability and side effect profile. Several large clinical trials of ARB are now under way to demonstrate their benefits in hypertension, heart failure, and type II diabetic nephropathy. PMID:10201883

Burnier, M; Brunner, H R

1999-04-01

93

NMDA receptor antagonists extend the sensitive period for imprinting.  

PubMed

Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting. PMID:10764906

Parsons, C H; Rogers, L J

2000-03-01

94

Vasopressin receptor antagonists, heart failure, and polycystic kidney disease.  

PubMed

The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization. PMID:25493947

Torres, Vicente E

2015-01-01

95

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

PubMed Central

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

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

2014-01-01

96

Comparative antagonist pharmacology at the native mouse bradykinin B2 receptor: radioligand binding and smooth muscle contractility studies  

PubMed Central

Background and purpose: The aim was to characterize the recently discovered non-peptide antagonist MEN16132 at the mouse B2 receptor, relative to other antagonists. Experimental approach: [3H]-BK binding experiments used mouse lung and ileum tissue membranes and antagonist potency was measured in the isolated ileum contractility assay. Key results: Two BK binding sites resulted from saturation and homologous competition experiments. A role for the B1 receptor was excluded because of the poor affinity of B1 receptor ligands (pIC50 <5). MEN16132, and the other reference antagonists, inhibited only one portion of BK specific binding, and the rank order of potency was (pIC50): Icatibant (lung 10.7; ileum 10.2)=MEN11270 (lung 10.4; ileum 9.9)=MEN16132 (lung 10.5; ileum 9.9). > LF16-0687 (lung 8.9; ileum 8.8) > FR173657 (lung 8.6; ileum 8.2). BK homologous curves performed with lung membranes after treatment with the antagonist MEN16132 or Icatibant (10 nM) displayed only the low affinity site. The functional antagonism by MEN16132 (pA2 9.4) and Icatibant (pA2 9.1), towards BK (control EC50 6.1 nM) induced ileum contractions, was concentration-dependent and surmountable, but the Schild plot slope was less than unity. Conclusions and Implications: In mouse tissue, radiolabelled BK recognizes two binding sites and B2 receptor antagonists can compete only for the higher affinity one. The pharmacological profile of the novel non-peptide antagonist MEN16132 indicates that it exhibits subnanomolar affinity and potency for the mouse B2 receptor and is suitable for further characterization in in vivo pathophysiological models. PMID:17179941

Meini, S; Cucchi, P; Bellucci, F; Catalani, C; Giuliani, S; Santicioli, P; Maggi, C A

2006-01-01

97

Negative Selection of CD4^+ CD8^+ Thymocytes by T-Cell Receptor Peptide Antagonists  

Microsoft Academic Search

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

Dawne M. Page; Jeff Alexander; Ken Snoke; Ettore Appella; Alessandro Sette; Stephen M. Hedrick; Howard M. Grey

1994-01-01

98

Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor  

PubMed Central

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

Perrey, David A.; German, Nadezhda A.; Gilmour, Brian P.; Li, Jun-Xu; Harris, Danni L.; Thomas, Brian F.; Zhang, Yanan

2013-01-01

99

Structure-function studies of agonist binding to the muscle-type nicotinic acetylcholine receptor and the development of a trifunctional non-competitive antagonist suitable for activity-dependent profiling  

E-print Network

The muscle-type nicotinic acetylcholine receptor (AChR) is a ligand-gated ion channel required for fast synaptic transmission at the neuromuscular junction. It is the archetype of the Cys-Loop superfamily of receptors and ...

Tantama, Mathew C

2008-01-01

100

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

PubMed

?-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

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

2014-09-01

101

"Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.  

PubMed

Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were found to be specific antagonists of receptor activation by thrombin. The effectiveness of these designed antagonists in blocking thrombin-induced platelet activation suggests a model for thrombin-receptor interaction and possible strategies for the development of novel antithrombotic agents. PMID:1310695

Hung, D T; Vu, T K; Wheaton, V I; Charo, I F; Nelken, N A; Esmon, N; Esmon, C T; Coughlin, S R

1992-02-01

102

Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor  

PubMed Central

BACKGROUND AND PURPOSE Understanding the role of the EP2 receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP2 receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP2 receptor over other EP receptors using a range of isolated tissue systems. EXPERIMENTAL APPROACH PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP1); ONO-AE1-259 and PGE2- induced relaxation of mouse and guinea pig trachea (EP2); PGE2-induced depolarization of guinea pig isolated vagus (EP3); PGE2-induced relaxation of human and rat trachea (EP4). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptor assays. KEY RESULTS In bioassay systems, where assessment of potency/selectivity is made against the ‘native’ receptor, PF-04418948 only acted as an antagonist of EP2 receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO-AE1-259 and PGE2 respectively. However, the affinity of PF-04418948 was not equal in the two preparations. CONCLUSIONS AND IMPLICATIONS Using a wide range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP2-receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP2 receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE2 and the role of EP2 receptors in health and disease. PMID:22747912

Birrell, Mark A; Maher, Sarah A; Buckley, James; Dale, Nicole; Bonvini, Sara; Raemdonck, Kristof; Pullen, Nick; Giembycz, Mark A; Belvisi, Maria G

2013-01-01

103

Investigation of the specificity of FK 888 as a tachykinin NK1 receptor antagonist.  

PubMed Central

1. A recently described peptide tachykinin (NK1) receptor antagonist, FK 888, was found to inhibit the electrically-evoked, tachykinin-mediated contractile responses of the rabbit iris sphincter in a concentration-dependent manner; the pIC50 value was 6.6 +/- 0.08. 2. Contractions induced by a selective NK1 receptor agonist, [Sar9,Met(O2)11]substance P, were inhibited competitively by FK 888; the pKB value was 7.1. 3. FK 888 (1 nM-100 microM) was without effect on the electrically-evoked, cholinergic response of the rabbit iris sphincter and the electrically-evoked, sympathetic response of the guinea-pig vas deferens. The contractions of the rabbit iris sphincter, induced by either carbachol (10 nM-30 microM) or noradrenaline (0.1-100 microM), were not affected by 10 microM FK 888. 4. FK 888 (1-30 microM) did not induce histamine release from rat peritoneal mast cells. 5. FK 888 (33 and 333 microM) was without effect on the electrically-evoked action potentials of the frog sciatic nerve. Thus, FK 888 is a moderately high affinity and selective tachykinin (NK1) receptor antagonist. PMID:7518299

Wang, Z. Y.; Tung, S. R.; Strichartz, G. R.; Hĺkanson, R.

1994-01-01

104

Angiotensin II receptor antagonists in the treatment of hypertension.  

PubMed

The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) includes recommendations for the assessment of overall cardiovascular risk and the need for active antihypertensive drug therapy. Once the decision to initiate antihypertensive drug therapy has been made, JNC-VI recommends one of three paths for the choice of initial therapy: one path for patients with uncomplicated hypertension, another for those with well-defined indications for certain drugs and a third path for patients with various concomitant conditions in which one or another drug has favorable effects. At this time, the place for the newest class of antihypertensive drugs, the angiotensin II receptor antagonists, remains uncertain. Currently, they are considered reasonable alternatives for patients who have a compelling need for an angiotensin-converting enzyme (ACE) inhibitor but develop a cough while taking this medication. When data from ongoing trials become available, angiotensin II receptor antagonists may prove to be a good choice for initial therapy in many patients because of the favorable side effect profile of this class of drugs. PMID:10507747

Kaplan, N M

1999-09-15

105

Evodiamine as a novel antagonist of aryl hydrocarbon receptor  

SciTech Connect

Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

Yu, Hui [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China) [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Department of Laboratory Medicine, The Affiliated Tenth People's Hospital, Tongji University, Shanghai 200072 (China); Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China)] [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Wang, Zhanli [College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014 (China)] [College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014 (China); Liang, Huaping, E-mail: huaping_liang@yahoo.com.cn [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China)] [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China)

2010-11-05

106

A search for selective antagonists at M2 muscarinic receptors.  

PubMed Central

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

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

1985-01-01

107

NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells.  

PubMed

BackgroundB cells are important effectors and regulators of adaptive and innate immune responses, inflammation and autoimmunity, for instance in anti-NMDA-receptor (NMDAR) encephalitis. Thus, pharmacological modulation of B-cell function could be an effective regimen in therapeutic strategies. Since the non-competitive NMDAR antagonist memantine is clinically applied to treat advanced Alzheimer`s disease and ketamine is supposed to improve the course of resistant depression, it is important to know how these drugs affect B-cell function.ResultsNon-competitive NMDAR antagonists impaired B-cell receptor (BCR)- and lipopolysaccharide (LPS)-induced B-cell proliferation, reduced B-cell migration towards the chemokines SDF-1ż and CCL21 and downregulated IgM and IgG secretion. Mechanistically, these effects were mediated through a blockade of Kv1.3 and KCa3.1 potassium channels and resulted in an attenuated Ca2+-flux and activation of Erk1/2, Akt and NFATc1. Interestingly, NMDAR antagonist treatment increased the frequency of IL-10 producing B cells after BCR/CD40 stimulation.ConclusionsNon-competitive NMDAR antagonists attenuate BCR and Toll-like receptor 4 (TLR4) B-cell signaling and effector function and can foster IL-10 production. Consequently, NMDAR antagonists may be useful to target B cells in autoimmune diseases or pathological systemic inflammation. The drugsż additional side effects on B cells should be considered in treatments of neuronal disorders with NMDAR antagonists. PMID:25477292

Simma, Narasimhulu; Bose, Tanima; Kahlfuß, Sascha; Mankiewicz, Judith; Lowinus, Theresa; Lühder, Fred; Schüler, Thomas; Schraven, Burkhart; Heine, Martin; Bommhardt, Ursula

2014-12-01

108

Angiotensin II receptor antagonists role in arterial hypertension.  

PubMed

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising. PMID:11986904

Hernández-Hernández, R; Sosa-Canache, B; Velasco, M; Armas-Hernández, M J; Armas-Padilla, M C; Cammarata, R

2002-03-01

109

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-?1 Receptors  

PubMed Central

2-Aminoethyl methylphosphonate (2-AEMP), an analog of GABA, has been found to exhibit antagonist activity at GABAA-?1 (also known as ?1 GABAC) receptors. The present study was undertaken to elucidate 2-AEMP's action and to test the activities of 2-AEMP analogs. Whole-cell patch-clamp techniques were used to record membrane currents in neuroblastoma cells stably transfected with human GABAA-?1 receptors. The action of 2-AEMP was compared with that of 1,2,5,6-tetrahydropyridin-4-yl methylphosphinic acid (TPMPA), a commonly used GABAA-?1 antagonist. With 10 ?M GABA, 2-AEMP's IC50 (18 ?M) differed by less than 2.5-fold from that of TPMPA (7 ?M), and results obtained were consistent with a primarily competitive mode of inhibition by 2-AEMP. Terminating the presentation of 2-AEMP or TPMPA in the presence of GABA produced a release from inhibition. However, the rate of inhibition release upon the termination of 2-AEMP considerably exceeded that determined with termination of TPMPA. Moreover, when presented at concentrations near their respective IC50 values, the preincubation period associated with 2-AEMP's onset of inhibition was much shorter than that for TPMPA. Analogs of 2-AEMP possessing a benzyl or n-butyl rather than a methyl substituent at the phosphorus atom, as well as analogs bearing a C-methyl substituent on the aminoethyl side chain, exhibited reduced potency relative to 2-AEMP. Of these analogs, only (R)-2-aminopropyl methylphosphonate significantly diminished the response to 10 ?M GABA. Structure-activity relationships are discussed in the context of molecular modeling of ligand binding to the antagonist binding site of the GABAA-?1 receptor. PMID:21810922

Xie, An; Yan, Jun; Yue, Lan; Feng, Feng; Mir, Fozia; Abdel-Halim, Heba; Chebib, Mary; Le Breton, Guy C.; Standaert, Robert F.; Qian, Haohua

2011-01-01

110

N-Oxide analogs of WAY-100635: new high affinity 5-HT1A receptor antagonists  

E-print Network

N-Oxide analogs of WAY-100635: new high affinity 5-HT1A receptor antagonists Sandrine Marchais 2 are well-known high affinity 5-HT1A receptor antagonists, which when labeled with carbon-11 (b and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3

Shen, Jun

111

Inhibition of tolerance to spinal morphine antinociception by low doses of opioid receptor antagonists  

Microsoft Academic Search

Ultra-low doses of opioid receptor antagonists inhibit development of chronic spinal morphine tolerance. As this phenomenon mechanistically resembles acute tolerance, the present study examined actions of opioid receptor antagonists on acute spinal morphine tolerance. In adult rats, administration of three intrathecal injections of morphine (15 ?g) at 90 min intervals produced a significant decline of the antinociceptive effect and loss of agonist

Benjamin McNaull; Tuan Trang; Maaja Sutak; Khem Jhamandas

2007-01-01

112

Systemic administration of MK-801, a non-competitive NMDA-receptor antagonist, elicits a behavioural deficit of rats in the Active Allothetic Place Avoidance (AAPA) task irrespectively of their intact spatial pretraining  

Microsoft Academic Search

Spatial orientation is considered to be an animal model of human cognitive functions. Efficient navigation is believed to require a brain representation of the environment. The role of NMDA-receptor-dependent neurotransmission in encoding spatial representations has been intensively studied; however, its involvement in organizing spatial information into neural representations is poorly understood. We tested the effect of NMDA-receptor blockade on the

Ales Stuchlík; Karel Vales

2005-01-01

113

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

PubMed

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

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

2012-10-30

114

Orexin receptor antagonists as therapeutic agents for insomnia  

PubMed Central

Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia. PMID:24416019

Equihua, Ana C.; De La Herrán-Arita, Alberto K.; Drucker-Colin, Rene

2013-01-01

115

Two Cases of H2-Receptor Antagonist Hypersensitivity and Cross-Reactivity  

PubMed Central

H2-receptor antagonists, such as cimetidine, ranitidine and famotidine, are some of the most commonly prescribed medications for gastric acid-related disorders. These compounds are generally well-tolerated and anaphylactic reactions to them are rare. Here, we report two cases of H2-receptor antagonist-induced anaphylactic reactions: the first presented with sudden dyspnea, sneezing, urticaria, and swelling of the eyelids after ranitidine intake. The second presented with sudden severe urticaria, facial swelling, chest discomfort, dizziness, and hypotension. Possible cross-reactivity with other H2-receptor antagonists was assessed by oral challenge and skin tests. To date, only a few reports addressing cross-reactivity among H2-receptor antagonists have been published. We review the literature and summarize the data available on drug cross-reactivity in H2-receptor antagonist hypersensitivity. PMID:21461253

Song, Woo-Jung; Kim, Min-Hye; Lee, Sang-Min; Kwon, Yong-Eun; Kim, Sae-Hoon; Cho, Sang-Heon; Min, Kyung-Up; Kim, You-Young

2011-01-01

116

Potential Clinical Implications of the Urotensin II Receptor Antagonists  

PubMed Central

Urotensin II (UII) binds to its receptor, UT, playing an important role in the heart, kidneys, pancreas, adrenal gland, and central nervous system. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, however, this constriction–dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome, and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) activity leading to smooth muscle cell proliferation and foam cell infiltration, insulin resistance (DMII), as well as inflammation, high blood pressure, and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases. PMID:21811463

Tsoukas, Philip; Kane, Émilie; Giaid, Adel

2011-01-01

117

Effects of a Novel Bradykinin B1 Receptor Antagonist and Angiotensin II Receptor Blockade on Experimental Myocardial Infarction in Rats  

PubMed Central

Background The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI) and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist after MI in rats. Methodology/Principal Findings Sprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either B1 receptor antagonist (BI-113823) or AT1 receptor antagonist (irbesartan) alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP); greater first derivative of left ventricular pressure (± dp/dt max), left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2) and collagen III. In addition, the cardiac up-regulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1) mRNA expression were not significantly affected by B1 receptor blockade. Conclusions/Significance The present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI. PMID:23236443

Wu, Dongmei; Lin, Xinchun; Bernloehr, Christian; Hildebrandt, Tobias; Doods, Henri

2012-01-01

118

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

SciTech Connect

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.

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

119

Optimal dosing characteristics of the angiotensin II receptor antagonist telmisartan.  

PubMed

An optimal antihypertensive drug produces superior blood pressure-lowering effects at established dosages, with an acceptably low incidence of side effects, and at a dosage interval that is convenient for patients (ideally, once daily). The angiotensin II receptor antagonist, telmisartan, meets these criteria. At doses of > or = 40 mg, this once-daily drug produces a statistically significant reduction in blood pressure. Ambulatory blood pressure monitoring (ABPM) and high trough-peak ratios attest to the smooth, consistent blood pressure-lowering effect of telmisartan at 40- and 80-mg dosages. Telmisartan also demonstrates a statistically superior antihypertensive effect toward the end of the dosing interval compared with amlodipine and losartan, and it has a side-effect profile comparable to that of placebo. In summary, the evidence suggests that telmisartan at dosages of 40 and 80 mg once daily satisfies the 3 criteria of an ideal antihypertensive agent, producing an effective and sustained response with placebo-like tolerability. PMID:10437738

Meredith, P A

1999-07-22

120

Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization.  

PubMed

The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified. PMID:19553113

Micheli, Fabrizio; Holmes, Ian; Arista, Luca; Bonanomi, Giorgio; Braggio, Simone; Cardullo, Francesca; Di Fabio, Romano; Donati, Daniele; Gentile, Gabriella; Hamprecht, Dieter; Terreni, Silvia; Heidbreder, Christian; Savoia, Chiara; Griffante, Cristiana; Worby, Angela

2009-08-01

121

Discovery of the first small-molecule opioid pan antagonist with nanomolar affinity at mu, delta, kappa, and nociceptin opioid receptors.  

PubMed

The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a known pharmacophore for mu opioid (MOP), kappa opioid (KOP), and delta opioid (DOP) receptor antagonists; however, it has not been explored in nociceptin opioid (NOP/ORL-1) receptor ligands. We recently found that the selective KOP antagonist JDTic, (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, containing this opioid antagonist pharmacophore, has significant binding affinity at the NOP receptor (Ki 16.67 ± 0.76 nM), with no intrinsic activity in the [(35)S]GTP?S functional assay. Since this is the first ligand containing the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore to have affinity for the NOP receptor, we explored the structural determinants of its NOP binding affinity. When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic. Interestingly, however, removal of the 3,4-dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold of JDTic increased the binding affinity at NOP by 10-fold (Ki 1.75 ± 0.74 nM) while maintaining comparable affinity for KOP, MOP, and DOP receptors (Ki 1.14 ± 0.63, 1.67 ± 0.6, and 19.6 ± 1.3 nM, respectively). In vitro functional efficacy studies using the [(35)S]GTP?S assay showed that this compound AT-076 functions as an antagonist at all four opioid receptors. Detailed characterization of the antagonist activity of AT-076 shows that it has a noncompetitive antagonist profile at the NOP and KOP receptors (insurmountable antagonism), but is a potent competitive antagonist at the MOP and DOP receptors, with Ke values 3-6-fold more potent than those of JDTic. AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes. Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076. PMID:25635572

Zaveri, Nurulain T; Journigan, V Blair; Polgar, Willma E

2015-04-15

122

Distinct effects of z-335, a new thromboxane A2 receptor antagonist, on rabbit platelets and aortic smooth muscle.  

PubMed

The effect of a novel thromboxane A2 receptor (TP) antagonist, (+/-)-sodium[2-(4-chlorophenylsulfonylaminomethyl)- indan-5-yl]acetate monohydrate (Z-335), on the U46619-induced responses was compared between rabbit platelets and aorta. Z-335 inhibited platelet shape change induced by U46619 with higher efficacy than SQ29548, a common TP antagonist. The U46619-induced platelet aggregation was inhibited by Z-335 in a noncompetitive manner, while it was competitively inhibited by SQ29548. Z-335 inhibited U46619-induced vasoconstriction of rabbit aorta with higher efficacy than SQ29548. The pA2 value of Z-335 in aortic vasoconstriction was significantly higher than in platelet shape change. The competitive binding study showed the higher pKi value of Z-335 against [3H]-SQ29548 binding in rabbit aortic smooth muscle cells than in platelets. These data suggest that Z-335 has useful characteristics of TP antagonism. PMID:17139194

Yoshida, Makoto; Sato, Yukari; Shimura, Tokuro; Ohkubo, Satoko; Honma, Shigeyoshi; Tanaka, Takao; Kurimoto, Tadashi; Nakahata, Norimichi

2007-01-01

123

Phosphorylation\\/Dephosphorylation of Androgen Receptor as a Determinant of Androgen Agonistic or Antagonistic Activity  

Microsoft Academic Search

Protein phosphorylation\\/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and ?-estradiol) stimulate receptor expression and phosphorylation and, as a result,

Long G. Wang; Xiao M. Liu; Willi Kreis; Daniel R. Budman

1999-01-01

124

Use of Enterally Delivered Angiotensin II Type Ia Receptor Antagonists to Reduce the Severity of Colitis  

PubMed Central

Background Renin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia receptor antagonists use, we hypothesized that use of angiotensin II type Ia receptor antagonists compounds which lack cell membrane permeability, and thus enteric absorption, would allow for direct enteral delivery at far higher concentrations than would be tolerated systemically, yet retain efficacy. Methods Based on the structure of the angiotensin II type Ia receptor antagonist losartan, deschloro-losartan was synthesized, which has extremely poor cell membrane permeability. Angiotensin II type Ia receptor antagonist efficacy was evaluated by determining the ability to block NF-?B activation in vitro. Dextran sodium sulfate colitis was induced in mice and angiotensin II type Ia receptor antagonist efficacy delivered transanally was assessed. Results In vitro, deschloro-losartan demonstrated near equal angiotensin II type Ia receptor blockade compared to losartan as well as another angiotensin II type Ia receptor antagonist, candesartan. In the dextran sodium sulfate model, each compound significantly improved clinical and histologic scores and epithelial cell apoptosis. Abundance of TNF-?, IL-1?, and IL6 mRNA were significantly decreased with each compound. In vitro and in vivo intestinal drug absorption, as well as measures of blood pressure and mucosal and colonic blood flow, showed significantly lower uptake of deschloro-losartan compared to losartan and candesartan. Conclusions This study demonstrated efficacy of high-dose angiotensin II type Ia receptor antagonists in this colitis model. We postulate that a specially designed angiotensin II type Ia receptor antagonist with poor oral absorption may have great potential as a new therapeutic agent for inflammatory bowel disease in the future. PMID:21399927

Okawada, Manabu; Koga, Hiroyuki; Larsen, Scott D.; Showalter, Hollis D.; Turbiak, Anjanette J.; Jin, Xiaohong; Lucas, Peter C.; Lipka, Elke; Hillfinger, John; Kim, Jae Seung

2011-01-01

125

The NMDA receptor antagonist MK-801 alters lipoprivic eating elicited by 2-mercaptoacetate.  

PubMed

Eating behavior is controlled, at least in part, by levels of circulating metabolic fuels such as glucose and free fatty acids, and drugs that interfere with the availability of these fuels can elicit eating. One such drug is 2-mercaptoacetate (2MA), an inhibitor of fatty acid oxidation. Evidence also suggests that NMDA receptors may mediate some aspects of normal eating and satiety. The present study was conducted in order to determine whether NMDA receptors may play a role in feeding elicited by 2MA. Rats received intraperitoneal injections of either saline, 2MA, the non-competitive NMDA receptor antagonist MK-801 or a combined injection of 2MA and MK-801, and subsequent intake of a fat-enriched, mash diet was measured at 1, 2, 3 and 4 h post-injection. Results showed that cumulative food intake was significantly increased by 2MA alone, as compared to saline controls, with most of the 2MA-elicited eating occurring during the first hour post-injection. While MK-801 alone did not alter food intake, it did have a biphasic effect on feeding elicited by 2MA. MK-801 initially suppressed and later enhanced eating elicited by 2MA. Although it is unclear whether MK-801 is acting centrally, peripherally or both to alter 2MA-induced eating, these results implicate NMDA receptors and the neurotransmitter glutamate in the regulation of lipid-associated eating and satiety. PMID:15639164

Duva, Mark A; Siu, Alan; Stanley, B Glenn

2005-01-17

126

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

SciTech Connect

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.

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

1986-03-05

127

Effects of aging on antagonist and agonist interactions with. beta. -adrenergic receptors on human leukocyte membranes  

SciTech Connect

Alterations in properties and/or coupling of ..beta..-adrenergic receptors might explain the diminished responsiveness to ..beta..-receptor agonists observed in aged humans. Polymorphonuclear (PMN) and mononuclear (MN) leukocytes were isolated on Percoll gradients from young or old healthy volunteers (25-34 and 60-76 yrs). Saturation isotherms of /sup 125/I-pindolol binding to PMN and MN membranes were generated. The affinities did not differ between the two age groups or cell types (52-61 pM). The number of receptors differed only on MN membranes (PMN young: 37 +/- 5.7, old: 44 +/- 6.7; MN young: 55 +/- 7.1, old: 122 +/- 23 fmol/mg protein; N = 6-8); however, this apparent increase became a decrease if the data were expressed in fmol/million cells (MN young: 0.82 +/- 0.12; old: 0.57 +/- 0.10) suggesting alterations in protein content or cell types rather than receptors in aged MN's. Agonist affinities, determined from isoproterenol competition curves in the absence and presence of GTP, were not different between the two age groups or cell types. In agreement with most previous reports, no change with aging in the properties of antagonist binding to ..beta..-adrenergic receptors on MN's was detected. However, in contrast with an earlier report, no changes in agonist binding or coupling of the receptor in MN's from the elderly were found. These observations were extended to PMN's and suggest that changes in ..beta..-adrenergic receptors may not underlie age-related decreases in isoproterenol responsiveness.

Zahniser, N.R.; Parker, D.C.; Bier-Laning, C.M.; Miller, J.A.; Gerber, J.G.; Nies, A.S.

1986-03-01

128

Discovery of 2-substituted benzoxazole carboxamides as 5HT 3 receptor antagonists  

Microsoft Academic Search

A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT3 receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT3A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT3 receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of

Zhicai Yang; David J. Fairfax; Jun-Ho Maeng; Liaqat Masih; Alexander Usyatinsky; Carla Hassler; Soshanna Isaacson; Kevin Fitzpatrick; Russell J. DeOrazio; Jianqing Chen; James P. Harding; Matthew Isherwood; Svetlana Dobritsa; Kevin L. Christensen; Jonathan D. Wierschke; Brian I. Bliss; Lisa H. Peterson; Cathy M. Beer; Christopher Cioffi; Michael Lynch; W. Martin Rennells; Justin J. Richards; Timothy Rust; Yuri L. Khmelnitsky; Marlene L. Cohen; David D. Manning

2010-01-01

129

Inhibition of radiation-induced polyuria by histamine receptor antagonists  

SciTech Connect

In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor.

Donlon, M.A.; Melia, J.A.; Helgeson, E.A.; Wolfe, W.W.

1986-03-01

130

Synthesis of Indole Derived Protease-Activated Receptor 4 Antagonists and Characterization in Human Platelets  

PubMed Central

Protease activated receptor-4 (PAR4) is one of the thrombin receptors on human platelets and is a potential target for the management of thrombotic disorders. We sought to develop potent, selective, and novel PAR4 antagonists to test the role of PAR4 in thrombosis and hemostasis. Development of an expedient three-step synthetic route to access a novel series of indole-based PAR4 antagonists also necessitated the development of a platelet based high-throughput screening assay. Screening and subsequent structure activity relationship analysis yielded several selective PAR4 antagonists as well as possible new scaffolds for future antagonist development. PMID:23776495

Young, Summer E.; Duvernay, Matthew T.; Schulte, Michael L.; Lindsley, Craig W.; Hamm, Heidi E.

2013-01-01

131

Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability  

PubMed Central

BACKGROUND AND PURPOSE Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H3 receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H4 receptor) to influence vestibular system function, using a selective H4 receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACH RT-PCR was used to assess the presence of H4 receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H4 receptor modulation in the rat vestibular system. KEY RESULTS The transcripts of H4 and H3 receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H4 receptor agonist 4-methylhistamine. Thioperamide, a H3/H4 receptor antagonist, exerted effects similar to those of H3 and H4 receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H4 receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONS H4 receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H4 receptors as pharmacological targets for the treatment of vestibular disorders. PMID:22624822

Desmadryl, G; Gaboyard-Niay, S; Brugeaud, A; Travo, C; Broussy, A; Saleur, A; Dyhrfjeld-Johnsen, J; Wersinger, E; Chabbert, C

2012-01-01

132

Inhaled muscarinic acetylcholine receptor antagonists for treatment of COPD.  

PubMed

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

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

2013-01-01

133

Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors.  

PubMed

We developed a structure-property-activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT(3A) receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (mu/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na(+) currents. A low mu/MW is compatible with drug-cumulation in apolar lipid rafts. This study confirms that size-intensive descriptors allow the development of compact SPAR models. PMID:19144451

Kornhuber, Johannes; Terfloth, Lothar; Bleich, Stefan; Wiltfang, Jens; Rupprecht, Rainer

2009-06-01

134

Allosteric modulation of muscarinic receptor signaling: alcuronium-induced conversion of pilocarpine from an agonist into an antagonist.  

PubMed

Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M(2) subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M(2)-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC(50, Alc) = 5.63) without any effect on the EC(50) of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pK(A, Alc) = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 microM alcuronium. Measuring guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in CHO-M(2) membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [(35)S]GTPgammaS binding (pIC(50, Alc) = 5.47) without shift in EC(50), whereas it competitively shifted the response to oxotremorine M (pK(A, Alc) = 5.97). [(3)H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist-a novel type of functional allosteric interaction. PMID:11961078

Zahn, Katrin; Eckstein, Niels; Tränkle, Christian; Sadée, Wolfgang; Mohr, Klaus

2002-05-01

135

Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology.  

PubMed

The GABA(A) agonists muscimol (1), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, gaboxadol, 3), and the partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 6a) and their respective 3-isothiazolol analogues thiomuscimol (2), thio-THIP (4), and thio-4-PIOL (7a) are ligands at the GABA(A) orthosteric (recognition) site. The structure-activity relationships (SARs) between these structures are key elements of a 3D-pharmacophore model for GABA(A) agonists and competitive antagonists [Frřlund, B.; Jřrgensen, A. T.; Tagmose, L.; Stensbřl, T. B.; Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem. 2002, 45, 2454-2468]. Prompted by this model, we now report the synthesis and SAR of a series of analogues of 7a, in which the 4-position of the 3-isothiazolol was substituted by alkyl or bulky aromatic groups such as naphthylmethyl and diphenylalkyl groups (7b-h). The compounds have been pharmacologically characterized using receptor binding assays and two-electrode voltage-clamped Xenopus oocytes expressing alpha1beta3gamma2S- and alpha4beta3delta-containing receptors. The compounds show SARs comparable with those of 6b-h but are generally 5-15 times more potent. The 2-naphthylmethyl, the 1-bromo-2-naphthylmethyl, and the 3,3-diphenylpropyl analogues, compounds 7e, 7f, and 7h, respectively, show affinity in the low-nanomolar range (K(i) 2-10 nM). Interestingly, 7e and 7h exhibited a mixed antagonist profile consisting of a noncompetitive component in the picomolar range and a competitive component at concentrations above 1 nM. This unique profile was shown not to be due to either use dependence or kinetic effects. This antagonist profile of 7e and 7h was particularly pronounced at alpha4beta3delta-containing GABA(A) receptors, which showed three- and 10-fold selectivity for 7h and 6h, respectively. PMID:16480274

Krehan, Dorte; Storustovu, Signe I; Liljefors, Tommy; Ebert, Bjarke; Nielsen, Birgitte; Krogsgaard-Larsen, Povl; Frřlund, Bente

2006-02-23

136

Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists  

PubMed Central

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

Pertwee, R.G.

2010-01-01

137

SDZ 205-557, a selective, surmountable antagonist for 5HT 4 receptors in the isolated guinea pig ileum  

Microsoft Academic Search

A selective antagonist for the recently characterized 5-HT4-receptor is lacking. The only surmountable antagonist available, ICS 205-930, is a weak antagonist and is far more potent at 5-HT3-than at 5-HT4 receptors. In this paper, SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) is characterized as the first potent, selective and surmountable antagonist at 5-HT4 receptors in the isolated guinea pig ileum.

Karl-Heinz Buchheit; Rainer Gamse; Hans-Jtirgen Pfannkuche

1992-01-01

138

Dipyrimidine Amines: A Novel Class of Chemokine Receptor Type 4 Antagonists with High Specificity  

PubMed Central

The C-X-C chemokine receptor type 4 (CXCR4)/stromal cell derived factor-1 (SDF-1 or CXCL12) interaction and the resulting cell signaling cascade play a key role in metastasis and inflammation. Based on the previously published CXCR4 antagonist 5 (WZ811), a series of novel non-peptidic anti-CXCR4 small molecules have been designed and synthesized to improve potency. Following a structure-activity profile around 5, more advanced compounds in the N, N'-(1, 4-phenylenebis(methylene)) dipyrimidin-2-amines series were discovered and shown to possess higher CXCR4 binding potential and specificity than 5. Compound 26 (508MCl) is the leading compound, and exhibits subnanomolar potency in three in vitro assays including competitive binding, Matrigel invasion, and G?i cyclic adenosine monophosphate (cAMP) modulation signaling. Furthermore, compound 26 displays promising effects by interfering with CXCR4 function in three mouse models: paw inflammation, Matrigel plug angiogenesis, and uveal melanoma micrometastasis. These data demonstrate that dipyrimidine amines are unique CXCR4 antagonists with high potency and specificity. PMID:21105715

Zhu, Aizhi; Zhan, Weiqiang; Liang, Zhongxing; Yoon, Younghyoun; Yang, Hua; Grossniklaus, Hans E.; Xu, Jianguo; Rojas, Mauricio; Lockwood, Mark; Snyder, James P.; Liotta, Dennis C.; Shim, Hyunsuk

2010-01-01

139

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

PubMed

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

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

140

Characterization of binding sites of a new neurotensin receptor antagonist, [3  

E-print Network

neuropeptide found in the central nervous system and peripheral tissues of numerous mammalian species (Emson et, a histamine H1 receptor antagonist (Schotte et al., 1986). In other species, including humans, rabbits

Paris-Sud XI, Université de

141

"Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.  

PubMed Central

Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were found to be specific antagonists of receptor activation by thrombin. The effectiveness of these designed antagonists in blocking thrombin-induced platelet activation suggests a model for thrombin-receptor interaction and possible strategies for the development of novel antithrombotic agents. Images PMID:1310695

Hung, D T; Vu, T K; Wheaton, V I; Charo, I F; Nelken, N A; Esmon, N; Esmon, C T; Coughlin, S R

1992-01-01

142

Quantifying the association and dissociation rates of unlabelled antagonists at the muscarinic M3 receptor  

PubMed Central

Slow receptor dissociation kinetics has been implicated in the long clinical duration of action of the muscarinic receptor antagonist tiotropium. However, despite the potential benefits of new drugs with slow dissociation kinetics, the rate parameters of new compounds are seldom measured due to technical difficulties and financial implications associated with radiolabeling multiple ligands. Here we describe the development and optimisation of a medium throughput assay which is capable of measuring the kinetic parameters of novel, unlabelled compounds. Radioligand binding studies were performed with membranes derived from CHO cells recombinantly expressing the human M3 muscarinic receptor. Initial characterisation of the radioligand [3H]-NMS yielded on and off rates of 4.1±0.2 × 108?M?1?min?1 and 0.015±0.0005?min?1, respectively. The specific binding of [3H]-NMS was measured over time in the presence and absence of several concentrations of unlabelled competitor compounds. These data were analysed using a competition kinetic model to provide on and off rates for the unlabelled competitor. Comparison of the kinetically derived Kd (koff/kon) with Ki values generated at equilibrium showed an excellent correlation (r2=0.99), providing good validation of the method. The on and off rates were also used in theoretical computer simulations to successfully predict the effect of incubation time on apparent IC50 values. This study demonstrates that a medium-throughput competition kinetic binding assay can be used to determine accurate on and off rates of unlabelled compounds, providing the opportunity to optimise for kinetic parameters early in the drug discovery process. PMID:16847442

Dowling, Mark R; Charlton, Steven J

2006-01-01

143

Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists  

Microsoft Academic Search

Current research on angiotensin II AT1-receptor antagonists (AIIRAs) and selected studies presented at the recent symposium held in Amsterdam, The Netherlands, on 6 June 1998, titled ‘Angiotensin II Receptor Antagonists are NOT all the Same’ are reviewed. AIIRAs offer a number of potential advantages over alternative antihypertensive agents acting via the renin-angiotensin-aldosterone system. They combine blood pressure-lowering effects at least

PS Sever

1999-01-01

144

5HT 1A receptor antagonist administration decreases cell proliferation in the dentate gyrus  

Microsoft Academic Search

This study investigated the action of 5-HT1A receptor antagonists on cell proliferation in the dentate gyrus of adult rats. Three antagonists (NAN-190, p-MPPI and WAY-100635) all produced a statistically significant ?30% reduction in the number of BrdU-immunoreactive cells in the dentate gyrus. This suggests that 5-HT1A receptor activity is important during naturally occurring cell proliferation in the dentate gyrus, and

Jason J Radley; Barry L Jacobs

2002-01-01

145

Discovery of antagonists of tick dopamine receptors via chemical library screening and comparative pharmacological analyses.  

PubMed

Ticks transmit a wide variety of disease causing pathogens to humans and animals. Considering the global health impact of tick-borne diseases, there is a pressing need to develop new methods for vector control. We are exploring arthropod dopamine receptors as novel targets for insecticide/acaricide development because of their integral roles in neurobiology. Herein, we developed a screening assay for dopamine receptor antagonists to further characterize the pharmacological properties of the two D?-like dopamine receptors (Isdop1 and Isdop2) identified in the Lyme disease vector, Ixodes scapularis, and develop a screening assay for receptor antagonists. A cell-based, cyclic AMP luciferase reporter assay platform was implemented to screen the LOPAC(1280) small molecule library for Isdop2 receptor antagonists, representing the first reported chemical library screen for any tick G protein-coupled receptor. Screening resulted in the identification of 85 "hit" compounds with antagonist activity at the Isdop2 receptor. Eight of these chemistries were selected for confirmation assays using a direct measurement of cAMP, and the effects on both Isdop1 and Isdop2 were studied for comparison. Each of these eight compounds showed antagonistic activity at both Isdop1 and Isdop2, although differences were observed regarding their relative potencies. Furthermore, comparison of the pharmacological properties of the tick dopamine receptors with that of the AaDOP2 receptor from the yellow fever mosquito and the human dopamine D? receptor (hD?) revealed species-specific pharmacological profiles of these receptors. Compounds influencing dopaminergic functioning, such as the dopamine receptor antagonists discovered here, may provide lead chemistries for discovery of novel acaricides useful for vector control PMID:23213654

Ejendal, Karin F K; Meyer, Jason M; Brust, Tarsis F; Avramova, Larisa V; Hill, Catherine A; Watts, Val J

2012-11-01

146

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement  

PubMed Central

Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1?h: ShA) or long (12?h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naďve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects. PMID:23303056

Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus

2013-01-01

147

Identification of a novel "almost neutral" micro-opioid receptor antagonist in CHO cells expressing the cloned human mu-opioid receptor.  

PubMed

The basal (constitutive) activity of G protein-coupled receptors allows for the measurement of inverse agonist activity. Some competitive antagonists turn into inverse agonists under conditions where receptors are constitutively active. In contrast, neutral antagonists have no inverse agonist activity, and they block both agonist and inverse agonist activity. The mu-opioid receptor (MOR) demonstrates detectable constitutive activity only after a state of dependence is produced by chronic treatment with a MOR agonist. We therefore sought to identify novel MOR inverse agonists and novel neutral MOR antagonists in both untreated and agonist-treated MOR cells. CHO cells expressing the cloned human mu receptor (hMOR-CHO cells) were incubated for 20 h with medium (control) or 10 microM (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK treatment generates a high degree of basal signaling and enhances the ability to detect inverse agonists. [(35)S]-GTP-gamma-S assays were conducted using established methods. We screened 21 MOR "antagonists" using membranes prepared from HERK-treated hMOR-CHO cells. All antagonists, including CTAP and 6beta-naltrexol, were inverse agonists. However, LTC-274 ((-)-3-cyclopropylmethyl-2,3,4,4alpha,5,6,7,7alpha-octahydro-1H-benzofuro[3,2-e]isoquinolin-9-ol)) showed the lowest efficacy as an inverse agonist, and, at concentrations less than 5 nM, had minimal effects on basal [(35)S]-GTP-gamma-S binding. Other efforts in this study identified KC-2-009 ((+)-3-((1R,5S)-2-((Z)-3-phenylallyl)-2-azabicyclo[3.3.1]nonan-5-yl)phenol hydrochloride) as an inverse agonist at untreated MOR cells. In HERK-treated cells, KC-2-009 had the highest efficacy as an inverse agonist. In summary, we identified a novel and selective MOR inverse agonist (KC-2-009) and a novel MOR antagonist (LTC-274) that shows the least inverse agonist activity among 21 MOR antagonists. LTC-274 is a promising lead compound for developing a true MOR neutral antagonist. PMID:19953652

Sally, Elliott J; Xu, Heng; Dersch, Christina M; Hsin, Ling-Wei; Chang, Li-Te; Prisinzano, Thomas E; Simpson, Denise S; Giuvelis, Denise; Rice, Kenner C; Jacobson, Arthur E; Cheng, Kejun; Bilsky, Edward J; Rothman, Richard B

2010-04-01

148

Analogues of ?-aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) substituted in the 2 position as GABAC receptor antagonists  

PubMed Central

?-Aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) have been shown to activate GABAC receptors. In this study, a range of C2, C3, C4 and N-substituted GABA and TACA analogues were examined for activity at GABAC receptors. The effects of these compounds were examined by use of electrophysiological recording from Xenopus oocytes expressing the human ?1 subunit of GABAC receptors with the two-electrode voltage-clamp method. trans-4-Amino-2-fluorobut-2-enoic acid was found to be a potent agonist (KD=2.43??M). In contrast, trans-4-amino-2-methylbut-2-enoic acid was found to be a moderately potent antagonist (IC50=31.0??M and KB=45.5??M). These observations highlight the possibility that subtle structural substitutions may change an agonist into an antagonist. 4-Amino-2-methylbutanoic acid (KD=189??M), 4-amino-2-methylenebutanoic acid (KD=182??M) and 4-amino-2-chlorobutanoic acid (KD=285??M) were weak partial agonists. The intrinsic activities of these compounds were 12.1%, 4.4% and 5.2% of the maximal response of GABA, respectively. These compounds more effectively blocked the effects of the agonist, GABA, giving rise to KB values of 53??M and 101??M, respectively. The sulphinic acid analogue of GABA, homohypotaurine, was found to be a potent partial agonist (KD=4.59??M, intrinsic activity 69%). It was concluded that substitution of a methyl or a halo group in the C2 position of GABA or TACA is tolerated at GABAC receptors. However, there was dramatic loss of activity when these groups were substituted at the C3, C4 and nitrogen positions of GABA and TACA. Molecular modelling studies on a range of active and inactive compounds indicated that the agonist/competitive antagonist binding site of the GABAC receptor may be smaller than that of the GABAA and GABAB receptors. It is suggested that only compounds that can attain relatively flat conformations may bind to the GABAC receptor agonist/competitive antagonist binding site. PMID:9422798

Chebib, Mary; Vandenberg, Robert J; Johnston, Graham A R

1997-01-01

149

Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.  

PubMed

A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D). PMID:20889341

Yang, Zhicai; Fairfax, David J; Maeng, Jun-Ho; Masih, Liaqat; Usyatinsky, Alexander; Hassler, Carla; Isaacson, Soshanna; Fitzpatrick, Kevin; DeOrazio, Russell J; Chen, Jianqing; Harding, James P; Isherwood, Matthew; Dobritsa, Svetlana; Christensen, Kevin L; Wierschke, Jonathan D; Bliss, Brian I; Peterson, Lisa H; Beer, Cathy M; Cioffi, Christopher; Lynch, Michael; Rennells, W Martin; Richards, Justin J; Rust, Timothy; Khmelnitsky, Yuri L; Cohen, Marlene L; Manning, David D

2010-11-15

150

Characterization of the binding of the first selective radiolabelled histamine H3-receptor antagonist, [125I]-iodophenpropit, to rat brain.  

PubMed Central

1. The binding of the first selective radiolabelled histamine H3-receptor antagonist [125I]-iodophenpropit to rat cerebral cortex membranes was characterized. 2. [125I]-iodophenpropit, radiolabelled to a high specific activity of 1900 Ci mmol-1, saturably bound to a single class of sites with a KD of 0.57 +/- 0.16 nM (n = 4) and Bmax of 268 +/- 119 fmol mg-1 protein. 3. Specific binding at a concentration below 1 nM represented 50 to 60% of total binding. 4. Binding of [125I]-iodophenpropit to rat cerebral cortex membranes was readily displaced by histamine H3-agonists and antagonists. In contrast, the inhibitory potencies of selective histamine H1- and H2-receptor ligands were very low. 5. [125I]-iodophenpropit was biphasically displaced by the histamine H3-receptor antagonists, burimamide and dimaprit, which may indicate the existence of histamine H3-receptor subtypes. Other histamine H3-receptor antagonists showed a monophasic displacement. 6. Competition binding curves of H3-agonists were biphasic and showed a rightward shift upon the addition of the nonhydrolysable GTP analogue, guanosine 5'-o-(3-thio) triphosphate (GTP gamma S; 100 microM) which implicates the interaction of histamine H3-receptors with G-proteins. The affinities of the H3-receptor antagonists iodophenpropit, thioperamide and burimamide were not altered by GTP gamma S. 7. Histamine competition binding curves were shifted to the right by different nucleotides (100 microM) with a rank order of potency GTP gamma S > Gpp(NH)p, GTP.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 5 PMID:7834183

Jansen, F P; Wu, T S; Voss, H P; Steinbusch, H W; Vollinga, R C; Rademaker, B; Bast, A; Timmerman, H

1994-01-01

151

Genetic Transfer of a Nonpeptide Antagonist Binding Site to a Previously Unresponsive Angiotensin Receptor  

Microsoft Academic Search

Mutational analysis based on the pharmacological differences between mammalian and amphibian angiotensin II receptors (AT receptors) previously identified 7 aa residues located in transmembrane domains (TMs) III (Val-108), IV (Ala-163), V (Pro-192, Thr-198), VI (Ser-252), and VII (Leu-300, Phe-301) of the rat AT receptor type 1b (rAT1b receptor) that significantly influenced binding of the nonpeptide antagonist Losartan. Further studies have

Hong Ji; Wei Zheng; Yue Zhang; Kevin J. Catt; Kathryn Sandberg

1995-01-01

152

Update on leukotriene receptor antagonists in preschool children wheezing disorders  

PubMed Central

Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS), is the cornerstone of asthma management. Since Leukotrienes (LTs) are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs) are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy. PMID:22734451

2012-01-01

153

Interleukin-1 receptor antagonist in normal and psoriatic epidermis.  

PubMed Central

The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-1ra) and IL-1 alpha were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity of the IL-1ra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-1ra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-1ra. The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-1ra was approximately 20 kD, slightly larger than monocyte-derived IL-1ra and equivalent to an intracellular variant of IL-1ra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-1ra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-1ra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-1ra and IL-1 alpha may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin. Images PMID:1386612

Hammerberg, C; Arend, W P; Fisher, G J; Chan, L S; Berger, A E; Haskill, J S; Voorhees, J J; Cooper, K D

1992-01-01

154

Substituted benzamides with conformationally restricted side chains. 2. Indolizidine derivatives as central dopamine receptor antagonists.  

PubMed

The substituted benzamides metoclopramide (1) and clebopride (3) are stimulants of gastric motility. They are also central dopamine receptor antagonists with 3 being the more potent. This is presumed to be due to an additional interaction of its N-benzyl group with the receptor. The effect of restricting the conformation of this group by replacing the N-benzylpiperidine side chain of 3 by phenyl-substituted quinolizidines and indolizidines has been investigated. Only the indolizidines had significant activity, the nature of which depended upon the orientation of the phenyl substituent. The 2 alpha-phenyl isomers 5d-h were potent central dopamine D2 receptor antagonists with 5h showing selectivity for the limbic system. The 2 beta-phenyl isomer 5c was a gastric motility stimulant devoid of significant central dopamine receptor antagonist activity. Implications on receptor models are discussed. PMID:2900897

King, F D; Hadley, M S; McClelland, C M

1988-09-01

155

NOP receptor mediates anti-analgesia induced by agonist-antagonist opioids.  

PubMed

Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ?90min after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia. PMID:24188792

Gear, R W; Bogen, O; Ferrari, L F; Green, P G; Levine, J D

2014-01-17

156

Palliation of Bone Cancer Pain by Antagonists of Platelet-Activating Factor Receptors  

PubMed Central

Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients. PMID:24637403

Kitayama, Tomoya; Kanematsu, Takashi; Uezono, Yasuhito; Dohi, Toshihiro

2014-01-01

157

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents  

PubMed Central

Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca+2 and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action. PMID:22190926

Vrachnis, Nikolaos; Malamas, Fotodotis M.; Sifakis, Stavros; Deligeoroglou, Efthymios; Iliodromiti, Zoe

2011-01-01

158

Importance of the N-terminal domain of the type II angiotensin antagonist sarmesin for receptor blockade.  

PubMed

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(ME)4]angiotensin II (sarmesin) with modifications at the N-terminus have been prepared by the solid-phase method and purified by reversed-phase HPLC. Substitution of the Sar1 residue of sarmesin with N,N-dimethyl-Gly, N-ethyl-Gly, aminoisobutyric, (methylamino)isobutyric, aminocaproic, and oxamic acids gave analogues that had the following respective antagonist activities (pA2) in the rat isolated uterus assay: less than 6, 6.9, 5.5, 6.0, less than 6, and 5.3. The additional substitution of Ile for Phe at the C-terminus of the latter four peptides gave pA2 values of 7.1, 5.1, less than 5, and 5. Substitution of the Arg2 residue of sarmesin with Nle or Sar abolished antagonist activity. These data emphasize the stringent and discriminating structural requirements in the N-terminal domain of sarmesin that endow this analogue with its antagonist properties and suggest the presence of defined steric constraints in this region of the molecule during receptor blockade. PMID:2455051

Matsoukas, J; Cordopatis, P; Belte, U; Goghari, M H; Ganter, R C; Franklin, K J; Moore, G J

1988-07-01

159

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

PubMed Central

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

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

1994-01-01

160

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

PubMed

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

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

2014-12-22

161

Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity.  

PubMed

Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation may serve as a new molecular target for screening androgen antagonists for the treatment of prostate cancer. PMID:10334909

Wang, L G; Liu, X M; Kreis, W; Budman, D R

1999-05-27

162

Analogues of the dopamine D2 receptor antagonist L741,626: Binding, Function and SAR  

PubMed Central

A series of analogues of the dopamine D2 receptor antagonist L741,626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity. PMID:17095222

Grundt, Peter; Husbands, Sarah Little Jane; Luedtke, Robert R.; Taylor, Michelle; Newman, Amy Hauck

2007-01-01

163

The cannabinoid CB 1 receptor antagonist CE prolongs spatial memory duration in a rat delayed radial arm maze memory task  

Microsoft Academic Search

The cannabinoid receptor system plays an integral role in learning and memory. Moreover, the cannabinoid CB1 receptor antagonist rimonabant has been found to improve performance in a variety of animal memory models. The present study tested whether a novel and potent cannabinoid CB1 receptor antagonist, CE, would prolong the duration of spatial memory. Rats were trained in a two-phase radial

Laura E. Wise; Philip A. Iredale; Aron H. Lichtman

2008-01-01

164

Montelukast, a Cysteinyl Leukotriene Receptor1 Antagonist, Dose and Time-Dependently Protects against Focal Cerebral Ischemia in Mice  

Microsoft Academic Search

Our previous studies showed that cysteinyl leukotriene receptor-1 (CysLT1) antagonist pranlukast has a neuroprotective effect on cerebral ischemia in rats and mice. However, whether the neuroprotective effect of pranlukast is its special action or a common action of CysLT1 receptor antagonists remains to be clarified. This study was performed to determine whether montelukast, another CysLT1 receptor antagonist, has the neuroprotective

Guo-Liang Yu; Er-Qing Wei; Shi-Hong Zhang; Hui-Ming Xu; Li-Sheng Chu; Wei-Ping Zhang; Qi Zhang; Zhong Chen; Ru-Huan Mei; Meng-Hui Zhao

2005-01-01

165

The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries  

PubMed Central

Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits potent orexigenic activity. In rodents, it exerts its actions by interacting with one receptor, MCH1 receptor which is expressed in many parts of the central nervous system (CNS). To study the physiological implications of the MCH system, we need to be able to block it locally and acutely. This necessitates the use of MCH1 receptor antagonists. While MCH1 receptor antagonists have been previously reported, they are mainly not accessible to academic research. We apply here a strategy that leads to the isolation of a high affinity and selective MCH1 receptor antagonist amenable to in vivo analyses without further chemical modifications. This antagonist, TPI 1361-17, was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight hundred thousand compounds in conditions that allow for the identification of only high-affinity compounds. TPI 1361-17 exhibited an IC50 value of 6.1 nM for inhibition of 1 nM MCH-induced Ca2+ mobilization and completely displaced the binding of [125I] MCH to rat MCH1 receptor. TPI 1361-17 was found specific, having no affinity for a variety of other G-protein coupled receptors and channels. TPI 1361-17 was found active in vivo since it blocked MCH-induced food intake by 75 %. Our results indicate that TPI 1361-17 is a novel and selective MCH1 receptor antagonist and is an effective tool to study the physiological functions of the MCH system. These results also illustrate the successful application of combinatorial library screening to identify specific surrogate antagonists in an academic setting. PMID:19041642

Nagasaki, Hiroshi; Chung, Shinjae; Dooley, Colette T.; Wang, Zhiwei; Li, Chunying; Saito, Yumiko; Clark, Stewart D; Houghten, Richard A.; Civelli, Olivier

2009-01-01

166

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

Microsoft Academic Search

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

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

1996-01-01

167

Identification of Receptor Ligands and Receptor Subtypes Using Antagonists in a Capillary Electrophoresis Single-Cell Biosensor Separation System  

NASA Astrophysics Data System (ADS)

A capillary electrophoresis system with single-cell biosensors as a detector has been used to separate and identify ligands in complex biological samples. The power of this procedure was significantly increased by introducing antagonists that inhibited the cellular response from selected ligand-receptor interactions. The single-cell biosensor was based on the ligand-receptor binding and G-protein-mediated signal transduction pathways in PC12 and NG108-15 cell lines. Receptor activation was measured as increases in cytosolic free calcium ion concentration by using fluorescence microscopy with the intracellular calcium ion indicator fluo-3 acetoxymethyl ester. Specifically, a mixture of bradykinin (BK) and acetylcholine (ACh) was fractionated and the components were identified by inhibiting the cellular response with icatibant (HOE 140), a selective antagonist to the BK B_2 receptor subtype (B_2BK), and atropine, an antagonist to muscarinic ACh receptor subtypes. Structurally related forms of BK were also identified based on inhibiting B_2BK receptors. Applications of this technique include identification of endogenous BK in a lysate of human hepatocellular carcinoma cells (Hep G2) and screening for bioactivity of BK degradation products in human blood plasma. The data demonstrate that the use of antagonists with a single-cell biosensor separation system aids identification of separated components and receptor subtypes.

Fishman, Harvey A.; Orwar, Owe; Scheller, Richard H.; Zare, Richard N.

1995-08-01

168

The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism.  

PubMed

In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G(q) and G(i) leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G(i) inhibits, whereas its coupling to G(q) stimulates, cell proliferation. Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G(q) coupling, displays agonistic properties on OTR/G(i) coupling, as shown by specific (35)S-labeled guanosine 5'-3-O-(thio) trisphosphate ([(35)S]GTPgammaS) binding. Moreover, atosiban, by acting on a G(i)-mediated pathway(,) inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21(WAF1/CIP1) induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a G(i) pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G(q)-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade. PMID:15705593

Reversi, Alessandra; Rimoldi, Valeria; Marrocco, Tiziana; Cassoni, Paola; Bussolati, Giovanni; Parenti, Marco; Chini, Bice

2005-04-22

169

Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo  

PubMed Central

Dysregulation of the 5-HT2A receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT2A receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT2A down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT2A receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT2A antagonists [ketanserin, altanserin, ?-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), ?-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT2A receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT2A antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT2A receptors and potentiated PCP-hyperlocomotion; the other 5-HT2A receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed. PMID:21737536

Yadav, Prem N.; Kroeze, Wesley K.; Farrell, Martilias S.

2011-01-01

170

Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD  

PubMed Central

In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective ?-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21198547

Moulton, Bart C; Fryer, Allison D

2011-01-01

171

5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure  

PubMed Central

Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2?mg/kg bid) or SB204741 (5?mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF. PMID:25667920

Janssen, Wiebke; Schymura, Yves; Novoyatleva, Tatyana; Luitel, Himal; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Weissmann, Norbert; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

2015-01-01

172

A peripherally selective diphenyl purine antagonist of the CB1 receptor  

PubMed Central

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

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

173

Proconvulsant action of two GABA(B) receptor antagonists is age-dependent.  

PubMed

Antagonists of GABA(B) receptors are expected to have proconvulsant action also in developing brain. Two antagonists (CGP55845 and CGP46381) were tested in a model of cortical epileptic afterdischarges (ADs) in 12-, 18- and 25-day-old rat pups with implanted electrodes. CGP55845 was dissolved in dimethylsulfoxide and the results demonstrated marked proconvulsant action of this solvent which masked possible action of the antagonist. Water soluble antagonist CGP46381 led to marked potentiation of ADs in 12-day-old animals, its action decreased with age, it was negligible in 25-day-old rats. Our results demonstrated important inhibitory role of GABA(B) receptors at very early stages of maturation. PMID:24329690

Mareš, P

2013-12-12

174

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

PubMed

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

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

175

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

NASA Astrophysics Data System (ADS)

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.

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

1998-04-01

176

Medicinal chemistry of P2X receptors: agonists and orthosteric antagonists.  

PubMed

In this work, we have highlighted data reported in the literature trying to draw a complete picture of the structures and biological activity of agonists and orthosteric antagonists of P2X receptors. Actually, only few P2X receptor agonists have been found and most of them are derived from modification of the natural ligand ATP and they are P2X receptor subtype unselective. In particular, BzATP (9) is one of the most potent P2X receptor agonists with EC50 value in the nanomolar range at some subtypes. Differently from agonists, P2X receptor antagonists belong to different chemical classes such as high molecular weight aryl polysulfonate molecules like suramin and its simplified derivatives and anthraquinone compounds. All these molecules proved to be non selective at P2X receptors, and they are endowed with micromolar activity and not favourable pharmacokinetic properties due to the presence of several charged groups. Also modification of the natural ligand ATP led to the discovery of P2X receptor antagonists like TNP-ATP (29), which, although not selective, showed high potency at P2X1, P2X3 (IC50 of 0.006 µM and 0.001 µM, respectively), and heteromeric P2X2/3 receptors. Also the dinucleotide inosine polyphosphate Ip5I (33) was found to be a potent and selective antagonist at P2X1 vs P2X3 receptors with IC50 = 0.003 µM. A significant improvement has been gained from the interest of pharmaceutical companies that in the last years discovered, through the use of high-throughput screening, potent and selective antagonists endowed with novel structures, some of which are currently in clinical trials for several therapeutic applications. PMID:25515515

Lambertucci, Catia; Dal Ben, Diego; Buccioni, Michela; Marucci, Gabriella; Thomas, Ajiroghene; Volpini, Rosaria

2015-01-01

177

Helokinestatin: A new bradykinin B 2 receptor antagonist decapeptide from lizard venom  

Microsoft Academic Search

Synthetic bradykinin antagonist peptides\\/peptoids have been powerful tools for delineating the roles of kinins in both normal physiology and in pathological states. Here, we report the identification of a novel, naturally occurring bradykinin B2 receptor antagonist peptide, helokinestatin, isolated and structurally characterized from the venoms of helodermatid lizards—the Gila monster (Heloderma suspectum) and the Mexican beaded lizard (Heloderma horridum). The

Hang Fai Kwok; Tianbao Chen; Martin O’Rourke; Craig Ivanyi; David Hirst; Chris Shaw

2008-01-01

178

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

Microsoft Academic Search

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

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

179

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

Microsoft Academic Search

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.

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

2007-01-01

180

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

PubMed

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, suggesting that AP18 may behave as a covalent antagonist of the TRPA1 ion-channel. PMID:19945872

Defalco, Jeff; Steiger, Daniel; Gustafson, Amy; Emerling, Daniel E; Kelly, Michael G; Duncton, Matthew A J

2010-01-01

181

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

PubMed Central

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

Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

2012-01-01

182

Cardioprotective Effects of Mineralocorticoid Receptor Antagonists at Reperfusion  

E-print Network

and the protection was abolished by co-treatment with inhibitors of the adenosine receptor, protein kinase C, PI3'-nucleotidase (CD73), as well as adenosine A2b receptor knock-out mice could no longer be protected, suggesting a role for adenosine and the A2b receptor in the mechanism. A 1 mg/kg bolus of canrenoate prior

Paris-Sud XI, Université de

183

Angiotensin II receptor antagonists role in arterial hypertension  

Microsoft Academic Search

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT1 receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT1 receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan,

R Hernández-Hernández; B Sosa-Canache; M Velasco; M J Armas-Hernández; M C Armas-Padilla; R Cammarata

2002-01-01

184

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

PubMed

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

Merlo Pich, Emilio; Melotto, Sergio

2014-01-01

185

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

PubMed Central

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

Merlo Pich, Emilio; Melotto, Sergio

2014-01-01

186

Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure  

PubMed Central

Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II) heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms associated with systolic heart failure will benefit from the addition of an aldosterone receptor antagonist to the standard therapies of angiotensin-converting enzyme inhibitors and beta-blockers. This review will address the pharmacologic basis of aldosterone receptor antagonists in patients with heart failure and the clinical impact of this therapy. PMID:21731887

Nappi, Jean M; Sieg, Adam

2011-01-01

187

Different types of receptor interaction of peptide and nonpeptide angiotensin II antagonists revealed by receptor binding and functional studies.  

PubMed

The pharmacological effects of angiotensin II (AII) are potently inhibited by several peptide and recently synthesized nonpeptide AII receptor antagonists. The interaction of sarcosine1, isoleucine8-AII (sarile), sarcosine1,O-methyltyrosine4-AII (sarmesin), and the nonpeptide AII antagonists 2-n-butyl-4-chloro-5- hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)- methyl]imidazole (DuP 753, Losartan potassium) and its metabolite 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidaz ole - 5-carboxylic acid (EXP3174) with AII binding sites was investigated in radioligand binding and functional studies. Sarile, sarmesin, DuP 753, and EXP3174 inhibited 125I-AII binding to rat lung tissue, with Ki values of 3.5, 16.1, 23.7, and 10.4 nM, respectively. The Hill coefficients of all displacement curves, except for sarile (nH, 1.45), were not significantly different from unity. In functional experiments using rabbit aorta, sarmesin and DuP 753 competitively inhibited the contractile response to AII, with pA2 values of 6.75 and 8.01, respectively. Sarile, in contrast, revealed noncompetitive antagonism, i.e., the maximum contractile force and the slope of the concentration-contractile force curve were significantly and concentration-dependently depressed. The concentration-contractile response curve for AII was shifted to the right in a parallel fashion in the presence of EXP3174 (3 nM to 1 microM); however, the maximum contractile force was significantly decreased, by 24%. The marked noncompetitive antagonism of sarile (3 nM) was reversed in the presence of increasing concentrations of sarmesin (30 nM to 30 microM) or DuP 753 (10 nM to 1 microM), whereas in the presence of increasing concentrations of EXP3174 (3-300 nM) a 25% depression in maximum contractile force persisted. Moreover, the reduction of the maximum contractile force by EXP3174 (10 nM) was concentration-dependently restored in the presence of increasing concentrations of DuP 753 (10 nM to 1 microM), indicating interaction with the same binding site. Whereas sarile (0.3-10 nM) did not affect the 125I-AII binding capacity in radioligand saturation experiments, a 54% reduction of Bmax was observed in the presence of 100 nM EXP3174. The data provide evidence that all antagonists inhibit the functional response to AII by interacting with a common binding site at the receptor. The noncompetitive behavior of sarile seems to be due to slow dissociation from this receptor site. An additional mechanism must be postulated for EXP3174. An allosteric interaction with the receptor, as suggested by the reduction in Bmax, may be, at least in part, responsible for the nonclassical antagonism of this compound. PMID:1614410

Wienen, W; Mauz, A B; Van Meel, J C; Entzeroth, M

1992-06-01

188

Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX2 receptor  

PubMed Central

Background and purpose: The OX2 receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX2 receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Experimental approach: The affinity of [3H]EMPA was assessed in membranes from HEK293-hOX2-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A-or orexin-B-induced accumulation of [3H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX2 receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala11,D-Leu15]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats. Key results: [3H]EMPA bound to human and rat OX2-HEK293 membranes with KD values of 1.1 and 1.4 nmol·L?1 respectively. EMPA competitively antagonized orexin-A-and orexin-B-evoked accumulation of [3H]IP at hOX2 receptors with pA2 values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [3H]EMPA for OX2 receptors. EMPA significantly reversed [Ala11,D-Leu15]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure. Conclusions and implications: EMPA is a high-affinity, reversible and selective OX2 receptor antagonist, active in vivo, which should prove useful for analysis of OX2 receptor function. PMID:19751316

Malherbe, P; Borroni, E; Gobbi, L; Knust, H; Nettekoven, M; Pinard, E; Roche, O; Rogers-Evans, M; Wettstein, JG; Moreau, J-L

2009-01-01

189

Combinatorial diffusion assay used to identify topically active melanocyte-stimulating hormone receptor antagonists.  

PubMed Central

alpha-Melanocyte-stimulating hormone (alpha-MSH) is implicated in pigmentation, central nervous system and immune system functions, growth, mitogenesis, and melanoma. Evaluation of these roles has been hindered by the lack of alpha-MSH antagonists. A combinatorial chemistry-based diffusion assay is used to find random tripeptides that antagonize normal frog and human melanoma MSH receptors and to identify pharmacological groups responsible for receptor interaction. The alpha-MSH antagonist D-Trp-Arg-Leu-NH2 is used to demonstrate directly the contribution of MSH to normal skin tone in frogs following injection or topical application. Images Fig. 1 Fig. 3 Fig. 4 Fig. 6 PMID:7708744

Quillan, J M; Jayawickreme, C K; Lerner, M R

1995-01-01

190

Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists.  

PubMed

The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s. PMID:15026042

Varnes, Jeffrey G; Gardner, Daniel S; Santella, Joseph B; Duncia, John V; Estrella, Melissa; Watson, Paul S; Clark, Cheryl M; Ko, Soo S; Welch, Patricia; Covington, Maryanne; Stowell, Nicole; Wadman, Eric; Davies, Paul; Solomon, Kimberley; Newton, Robert C; Trainor, George L; Decicco, Carl P; Wacker, Dean A

2004-04-01

191

Structure-activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 1.  

PubMed

A structurally unique and new class of opioid receptor antagonists (OpRAs) that bear no structural resemblance with morphine or endogenous opioid peptides has been discovered. A series of carboxamido-biaryl ethers were identified as potent receptor antagonists against mu, kappa and delta opioid receptors. The structure-activity relationship indicated para-substituted aryloxyaryl primary carboxamide bearing an amine tether on the distal phenyl ring was optimal for potent in vitro functional antagonism against three opioid receptor subtypes. PMID:17720493

Takeuchi, Kumiko; Holloway, William G; McKinzie, Jamie H; Suter, Todd M; Statnick, Michael A; Surface, Peggy L; Emmerson, Paul J; Thomas, Elizabeth M; Siegel, Miles G; Matt, James E; Wolfe, Chad N; Mitch, Charles H

2007-10-01

192

Molecular mechanisms and binding site location for the noncompetitive antagonist crystal violet on nicotinic acetylcholine receptors.  

PubMed

We investigated the molecular mechanisms and the binding site location for the fluorophor crystal violet (CrV), a noncompetitive antagonist of the nicotinic acetylcholine receptor (AChR). To this end, radiolabeled competition binding, fluorescence spectroscopy, Schild-type analysis, patch-clamp recordings, and molecular dynamics approaches were used. The results indicate that (i) CrV interacts with the desensitized Torpedo AChR with higher affinity than with the resting state at several temperatures (5-37 degrees C); (ii) CrV-induced inhibition of the phencyclidine (PCP) analogue [(3)H]thienylcyclohexylpiperidine binding to the desensitized or resting AChR is mediated by a steric mechanism; (iii) tetracaine inhibits CrV binding to the resting AChR, probably by a steric mechanism; (iv) barbiturates modulate CrV binding to the resting AChR by an allosteric mechanism; (v) CrV itself induces AChR desensitization; (vi) CrV decreases the peak of macroscopic currents by acting on the resting AChR but without affecting the desensitization rate from the open state; and (vii) two tertiary amino groups from CrV may bind to the alpha1-Glu(262) residues (located at position 20') in the resting state. We conclude that the CrV binding site overlaps the PCP locus in the resting and desensitized state. The noncompetitive action of CrV may be explained by an allosteric mechanism in which the binding of CrV to the extracellular mouth of the resting receptor leads to an inhibition of channel opening. Binding of CrV probably increases desensitization of the resting channel and stabilizes the desensitized state. PMID:16475790

Arias, Hugo R; Bhumireddy, Pankaj; Spitzmaul, Guillermo; Trudell, James R; Bouzat, Cecilia

2006-02-21

193

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

PubMed

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

Vyas, V K; Ghate, M

2010-12-01

194

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

PubMed

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

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

195

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

PubMed

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

Winrow, C J; Renger, J J

2014-01-01

196

Rational Design of Potent Antagonists to the Human Growth Hormone Receptor  

NASA Astrophysics Data System (ADS)

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

1992-06-01

197

Effects of cannabinoid receptor antagonists on maintenance and reinstatement of methamphetamine self-administration in rhesus monkeys  

Microsoft Academic Search

Cannabinoid receptor antagonists have shown some promise as treatments capable of reducing abuse and relapse to a number of abused drugs. In rodents, such effects have been observed with methamphetamine self-administration. However, the effects of cannabinoid receptor antagonists on methamphetamine self-administration and relapse have not been studied in primates. In the present study, rhesus monkeys were trained to respond on

Charles W. Schindler; Leigh V. Panlilio; Joanne P. Gilman; Zuzana Justinova; V. Kiran Vemuri; Alex Makriyannis; Steven R. Goldberg

2010-01-01

198

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

Microsoft Academic Search

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

Stanley M Crain; Ke-Fei Shen

2000-01-01

199

Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents – toward an understanding of their favorable tolerability  

Microsoft Academic Search

Summary.   Studies in experimental models have suggested that NMDA receptor antagonists may have utility in the treatment of a wide\\u000a variety of neurological and psychiatric disorders. However, clinical trials have not been encouraging largely because the\\u000a antagonists evaluated to date have exhibited unacceptable neurobehavioral side effects. In animals, therapeutic doses of some\\u000a low-affinity channel blocking (uncompetitive) NMDA receptor antagonists are

M. A. Rogawski

2000-01-01

200

Novel thiazole-thiophene conjugates as adenosine receptor antagonists: Synthesis, biological evaluation and docking studies.  

PubMed

Here we report novel thiazole-thiophene conjugates as adenosine receptor antagonists. All the molecules were evaluated for their binding affinity for adenosine receptors. Most of the molecules were found to interact with the A1, A2A and A3 adenosine receptor subtypes with good affinity values. The most potent and selective compound 8n showed an A3Ki value of 0.33?M with selectivity ratios of >90 versus the A1 and >30 versus the A2 subtypes. For compound 8n docking studies into the binding site of the A3 adenosine receptor are provided to visualize its binding mode. PMID:25686851

Pandya, Dhaivat H; Sharma, Jayesh A; Jalani, Hitesh B; Pandya, Amit N; Sudarsanam, V; Kachler, Sonja; Klotz, Karl Norbert; Vasu, Kamala K

2015-03-15

201

Design and synthesis of potential dual NK(1)/NK(3) receptor antagonists.  

PubMed

The tachykinin NK1 and NK3 receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile phenylglycine central core was synthesized and tested in vitro as dual NK1/NK3 receptor antagonists. From this series emerged compounds with good NK1 receptor affinity, although only modest dual NK1/NK3 receptor affinity was observed with one of these analogs. PMID:24374277

Hanessian, Stephen; Babonneau, Vincent; Boyer, Nicolas; Mannoury la Cour, Clotilde; Millan, Mark J; De Nanteuil, Guillaume

2014-01-15

202

Enantiomeric Propanolamines as selective N-Methyl-d-aspartate 2B Receptor Antagonists  

PubMed Central

Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11–64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30–100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties. PMID:18800760

Tahirovic, Yesim A.; Geballe, Matthew; Gruszecka-Kowalik, Ewa; Myers, Scott J.; Lyuboslavsky, Polina; Le, Phuong; French, Adam; Irier, Hasan; Choi, Woo-baeg; Easterling, Keith; Yuan, Hongjie; Wilson, Lawrence J.; Kotloski, Robert; McNamara, James O.; Dingledine, Raymond; Liotta, Dennis C.; Traynelis, Stephen F.; Snyder, James P.

2011-01-01

203

Chronic peripheral administration of the angiotensin II AT 1 receptor antagonist Candesartan blocks brain AT 1 receptors  

Microsoft Academic Search

Brain Angiotensin II, through stimulation of brain AT1 receptors, regulates pituitary hormones and autonomic activity. We have administered the insurmountable AT1 antagonist Candesartan, s.c. via osmotic minipumps for 14 days, to determine whether peripheral chronic AT1 blockade affects AT1 receptor binding and mRNA in the brain. Peripherally administered Candesartan (0.1, 0.5 or 1.0 mg\\/kg per day) inhibits AT1 binding in

Yasuaki Nishimura; Takeshi Ito; Kwang-Lae Hoe; Juan M. Saavedra

2000-01-01

204

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

PubMed Central

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

van Zwieten, P.A.

2006-01-01

205

Molecular electrostatic potentials in aromatic substituted 4-hydroxyquino-2-lones: Glycine\\/NMDA receptor antagonists  

Microsoft Academic Search

Hydroxyquinolone derivatives have proven to be useful for inhibition at the glycine binding site of N-methyl-D-aspartate (NMDA)\\u000a receptor. In this work the electronic structure, molecular electrostatic potential (MESP) and vibrational characteristics\\u000a of a set of C3 substituted 4-hydroxyquino-2-lone (HQ) derivatives, which act as Glycine\\/NMDA receptor antagonists, have been investigated\\u000a using the density functional calculations. In the optimized structures a substituent

Kaustubh A. Joshi; Dinannath D. Patil; Shridhar P. Gejji

2009-01-01

206

Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y 13 receptor  

Microsoft Academic Search

We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxal-5?-phosphate-6-azo-phenyl-2,4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Y13 nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing G?16 protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5?-alkyl phosphonate analogues were

Yong-Chul Kim; Jung-Sun Lee; Katrin Sak; Frederic Marteau; Liaman Mamedova; Jean-Marie Boeynaems; Kenneth A. Jacobson

2005-01-01

207

Adenosine A 1 receptor antagonist versus montelukast on airway reactivity and inflammation  

Microsoft Academic Search

Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A1 receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A1 receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared

Ahmed Nadeem; Peter C. M. Obiefuna; Constance N. Wilson; S. Jamal Mustafa

2006-01-01

208

Molecular determinants of agonist and antagonist signaling through the IL-36 receptor.  

PubMed

The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36?, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1. PMID:24935927

Günther, Sebastian; Sundberg, Eric J

2014-07-15

209

SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor  

Microsoft Academic Search

Based on both binding and functional data, this study intro- duces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki 5 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki 5 400 nM) for both the rat

MURIELLE RINALDI-CARMONA; FRANCIS BARTH; JEAN-MARIE DEROCQ; CHRISTIAN CONGY; DIDIER OUSTRIC; MARTINE SARRAN; BERNARD CALANDRA; MARIELLE PORTIER; DAVID SHIRE; JEAN-CLAUDE BRELIERE

210

Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions  

SciTech Connect

Autoradiographic studies localize (/sup 3/H)bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. (/sup 3/H)Bradykinin labeling is also observed over myocardinal/coronary visceral afferent fibers. The localization of (/sup 3/H)bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradkykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models.

Steranka, L.R.; Manning, D.C.; DeHaas, C.J.; Ferkany, J.W.; Borosky, S.A.; Connor, J.R.; Vavrek, R.J.; Stewart, J.M.; Snyder, S.H.

1988-05-01

211

Interactive effects of neurohypophyseal neuropeptides with receptor antagonists on passive avoidance behavior: mediation by a cerebral neurohypophyseal hormone receptor?  

PubMed Central

The neurohypophyseal neuropeptides (Arg8)-vasopressin (AVP) and [pGlu4,Cyt6]AVP-(4-8) (where pGlu is pyroglutamic acid and Cyt is cystine) facilitate the retention of one-trial-learning passive avoidance behavior in rats when administered into the cerebral ventricle immediately after the learning trial. The fragment [pGlu4,Cyt6]AVP-(4-8) was considerably more effective than AVP. Oxytocin (OXT) and [pGlu4,Cyt6]OXT-(4-8) have the opposite effect and attenuate passive avoidance behavior also when administered into the cerebral ventricle after the learning trial. Again the fragment was more active than the parent molecule. The ancient arginine-containing neurohypophyseal hormone vasotocin in "high" doses (10ng) had a vasopressin-like effect and in "low" doses (0.1 ng) had an OXT-like effect on passive avoidance behavior. Because both vasopressinergic (V1) and oxytocinergic receptors have been demonstrated in the central nervous system, we asked whether specific antagonists of the V1, V2, and OXT receptor could antagonize the effects of these neuropeptides on passive avoidance behavior. The three antagonists were approximately equally active in blocking the effect of vasopressin, whereas the fragment [pGlu4]AVP-(4-8) and the high dose of vasotocin were more readily blocked by the OXT antagonist. The attenuating effect of OXT, the fragment [pGlu4,Cyt6]OXT-(4-8), and the low dose of vasotocin was markedly reduced by the OXT antagonist. This effect could also be reduced by pretreatment with the V1 antagonist but not with the V2 antagonist. These results suggest the existence of a separate neurohypophyseal hormone receptor complex in the brain affecting memory processes that differs from the peripheral V1, V2, and OXT receptor. Images PMID:1847526

de Wied, D; Elands, J; Kovács, G

1991-01-01

212

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

SciTech Connect

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.

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

213

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 ...

214

Effect of the 5HT 3 receptor antagonists, MDL72222 and ondansetron on morphine place conditioning  

Microsoft Academic Search

The purpose of the present study was to reassess the original findings of Carboni et al. (1988) who suggested that 5-HT3 receptor antagonists may block morphine-induced place conditioning in rats. These workers used a biased protocol with treatments allocated to compartments based on initial preference. In the present study we have adopted an unbiased approach with treatments randomly assigned to

Guy A. Higgins; Narges Joharchi; Peter Nguyen; Edward M. Sellers

1992-01-01

215

Differential expression of interleukin 1 receptor antagonist isoforms in human intestinal epithelial cells  

Microsoft Academic Search

Background & Aims: Regulatory cytokines mediate intestinal epithelial cell (IEC) participation in mucosal immune responses. The aim of this study was to investigate the expression of secretory and intracellular isoforms of interleukin 1 receptor antagonist (IL-1Ra) in human primary IECs and carcinoma-derived cell lines. Methods: Primary IECs were isolated from patients with Crohn's disease or ulcerative colitis and from normal

Ulrich Böcker; Aderson Damiăo; Lisa Holt; Dong Soo Han; Christian Jobin; Asit Panja; Lloyd Mayer; R. Balfour Sartor

1998-01-01

216

Corresponding author: Didier PELAPRAT Neurotensin receptor antagonist administered during cocaine withdrawal  

E-print Network

Corresponding author: Didier PELAPRAT 1 Neurotensin receptor antagonist administered during cocaine: Neurotensin and cocaine sensitization Abstract: 236 words Text pages (including references): 30 pages Text-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when

Paris-Sud XI, Université de

217

Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide  

SciTech Connect

The present study was undertaken in order to determine whether chronic,long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats it was of interest to determine whether PLG would modulate antagonists-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 days from birth with SCH-23390, a selective dopamine D1 antagonist; or spiroperidol, a selective dopamine D2 antagonists; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG, in combination with the other treatments. Animals were decapitated at 5, 8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of ({sup 3}H) SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for ({sup 3}H) SCH-23390 binding, and no change in the K{sub D}. Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of ({sup 3}H) spiroperidol to striatal homogenates by 70-80%.

Saleh, M.I.M.

1988-01-01

218

New benzoyl urea derivatives as novel NR2B selective NMDA receptor antagonists.  

PubMed

A novel series of benzoyl urea derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substitution of the piperidine ring on the biological activity of the compounds was studied. Compound 9 was active in the formalin test in mice. PMID:17020160

Borza, I; Greiner, I; Kolok, S; Galgóczy, K; Ignácz-Szendrei, Gy; Horváth, Cs; Farkas, S; Gáti, T; Háda, V; Domány, Gy

2006-09-01

219

Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716  

Microsoft Academic Search

Social short-term memory in rodents is based on the recognition of a juvenile by an adult conspecific when the juvenile is presented on two successive occasions. Cannabimimetics are claimed to induce memory deficits in both humans and animals. In the brain, they mainly bind to CB1 receptors for which anandamide is a purported endogenous ligand. SR 141716, a specific antagonist

J.-P. Terranova; J.-J. Storme; N. Lafon; A Pério; M. Rinaldi-Carmona; G. Le Fur; P. Soubrié

1996-01-01

220

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...

221

BMS-189453, a Novel Retinoid Receptor Antagonist, Is a Potent Testicular Toxin  

Microsoft Academic Search

BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors a, b, and g. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg\\/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degenera- tion and atrophy at all doses. Significant overt signs

Gene E. Schulze; Richard J. Clay; Lawrence E. Mezza; Carla L. Bregman; Robert A. Buroker; Jerry D. Frantz

2001-01-01

222

Bisphenol-A, an Environmental Contaminant that Acts as a Thyroid Hormone Receptor Antagonist in Vitro,  

E-print Network

Bisphenol-A, an Environmental Contaminant that Acts as a Thyroid Hormone Receptor Antagonist the importance of thyroid hormone (TH) in brain development, it is of potential concern that a wide variety) THYROID HORMONE (TH) is essential for normal brain development in both humans (1, 2) and animals (3

Zoeller, R. Thomas

223

Successful treatment of resistant acromegaly with a growth hormone receptor antagonist  

Microsoft Academic Search

Background\\/objective: Pegvisomant is a pegylated analogue of human GH and functions as a potent GH receptor antagonist. This novel mode of action gives it the potential to achieve biochemical control in patients with acromegaly whose disease activity cannot be satisfactorily controlled by conventional therapy. We have documented the clinical details of seven patients with residual active acromegaly after surgery and\\/or

W M Drake; C Parkinson; S A Akker; J P Monson; G M Besser; P J Trainer

2001-01-01

224

Discovery of melanin-concentrating hormone receptor R1 antagonists using high-throughput synthesis.  

PubMed

A structure-activity study on benzylpiperidine 1 was accomplished by utilizing high-throughput synthesis. Three focused libraries were designed and synthesized to quickly develop SAR. Further optimization led to the discovery of compound 2, an MCH receptor R1 antagonist with over 400-fold improvement in biological activity over the original lead. PMID:15698800

Su, Jing; McKittrick, Brian A; Tang, Haiqun; Czarniecki, Michael; Greenlee, William J; Hawes, Brian E; O'Neill, Kim

2005-03-01

225

Stereoselective synthesis of (-)-hydroxyclemastine as a versatile intermediate for the H1 receptor antagonist clemastine.  

PubMed

Hydroxyclemastine was targeted as a versatile analogue of clemastine with H1 receptor antagonist activity. Stereoselective synthesis of (-)-hydroxyclemastine was performed in which the key step was chelation-controlled diastereoselective 1,2-addition of Grignard reagent to alpha-alkoxyketone. PMID:18254238

Jung, Jung Wha; Kim, Hee-Doo

2007-12-01

226

Effect of AT 1 angiotensin receptor antagonist on lipid peroxidation and antioxidative defense in diabetic kidney  

Microsoft Academic Search

The effects of losartan potassium, an AT1 angiotensin receptor antagonist on lipid peroxidation and activities of superoxide dismutase and catalase in the kidney of streptozotocin-diabetic rats were studied. Experimental diabetes resulted in an increase of malondialdehyde content of the kidneys and decreases of superoxide dismutase and catalase activity in this organ after 6 and 12 weeks. Administration of losartan potassium

K. K?dziora-Kornatowska; M. Luciak; J. B?aszczyk; W. Pawlak; J. K?dziora

2000-01-01

227

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

PubMed

Ligands that selectively block P2X3 receptors localized on nociceptive sensory fibres may be useful for the treatment of chronic pain conditions including neuropathic pain, migraine, and inflammatory pain. With the aim at exploring the suitability of adenine moiety as a scaffold for the development of antagonists of this receptor, a series of 9-benzyl-2-aminoadenine derivatives were designed and synthesized. These new compounds were functionally evaluated at rat or human P2X3 receptors expressed in human embryonic kidney (HEK) cells and on native P2X3 receptors from mouse trigeminal ganglion sensory neurons using patch clamp recording under voltage clamp configuration. The new molecules behaved as P2X3 antagonists, as they rapidly and reversibly inhibited (IC50 in the low micromolar range) the membrane currents induced via P2X3 receptor activation by the full agonist ?,?-methyleneATP. Introduction of a small lipophilic methyl substituent at the 6-amino group enhanced the activity, in comparison to the corresponding unsubstituted derivative, resulting in the 9-(5-iodo-2-isopropyl-4-methoxybenzyl)-N(6)-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC50 = 1.74 ± 0.21 ?M. PMID:23688699

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

2013-07-01

228

Cerebellar GABAA receptor selective for a behavioural alcohol antagonist  

Microsoft Academic Search

BENZODIAZEPINES are widely prescribed anxiolytics and anti-convulsants which bind with high affinity to sites on the GABAA receptor\\/Cl- channel complex and potentiate the effect of the neurotransmitter GABA (gamma-aminobutyric acid)1,2. The heterogeneity of benzodiazepine recognition sites in the central nervous system1,3,4 was revealed by studies showing different classes of GABAA receptor subunits (classes alpha, beta and gamma)5-7 and variant subunits

Hartmut Lüddens; Dolan B. Pritchett; Martin Köhler; Iris Killisch; Kari Keinänen; Hannah Monyer; Rolf Sprengel; Peter H. Seeburg

1990-01-01

229

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

PubMed Central

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

Heidbreder, Christian A.; Newman, Amy H.

2011-01-01

230

Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms.  

PubMed

Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30-80 Hz) power. MK-801 (0.05-0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose-response curve; at higher doses (0.3-1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130-180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5-4 Hz) power at higher doses. PCP (1.25-10 mg/kg) and ketamine (2.5-30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10-30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1-10 mg/kg) and DOI (0.5-2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition. PMID:24907590

Hiyoshi, Tetsuaki; Kambe, Daiji; Karasawa, Jun-ichi; Chaki, Shigeyuki

2014-10-01

231

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

SciTech Connect

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.

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

2013-07-01

232

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

PubMed

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

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

233

Inhibition by histamine H1 receptor antagonists of endogenous glibenclamide-sensitive K+ channels in follicle-enclosed Xenopus oocytes.  

PubMed

Effects of histamine receptor ligands on the glibenclamide-sensitive K+ currents induced by K+ channel openers, cromakalim and Y-26763, were examined in follicle-enclosed Xenopus oocytes. Histamine H1 receptor antagonists, promethazine, dimethindene and chlorpheniramine all decreased cromakalim-induced K+ currents with IC50 values of 31.5 microM, 29.5 microM and 138 microM, respectively. These compounds also blocked Y-26763-induced K+ currents with comparable IC50 values. Histamine (1 mM) and histamine H2 receptor antagonists, cimetidine (0.5 mM) and ranitidine (1 mM) had little effect on these K+ currents. These results suggest that histamine H1 receptor antagonists inhibit glibenclamide-sensitive K+ currents by a mechanism other than the histamine H1 receptor antagonism. The inhibitory effects might explain, in part, the reported actions of histamine H1 receptor antagonists in ischemia. PMID:7907990

Sakuta, H

1994-01-01

234

Central administration of GPR55 receptor agonist and antagonist modulates anxiety-related behaviors in rats.  

PubMed

G-protein-coupled receptor 55 (GPR55) has been proposed as an atypical cannabinoid receptor, which is activated by lysophosphatidylinositols and some synthetic or endogenous cannabinoid molecules. The exact role of GPR55 receptors in the central nervous system especially in anxiety needs to be evaluated. In this study, the effects of intracerebroventricular (i.c.v.) administration of agonist and antagonist of GPR55 receptor on anxiety-related behaviors in rats were investigated. Here, O-1602 (GPR55 agonist) at the doses of 0.2, 1, and 5 ?g/rat increased %OAT and %OAE but not the locomotor activity, showing an anxiolytic response, whereas i.c.v. injection of ML193 (GPR55 antagonist) at the doses of 0.1 and 1 ?g/rat increased anxiety-like behaviors while causing locomotor impairment. The antagonistic effect of ML193 on the anxiolytic-like effect of O-1602 was also evaluated. The results showed that ML193 decreased the anxiolytic-like effect of O-1602. Based on these results, it may be concluded that central GPR55 may have a role in modulation of anxiety-like behaviors in rats. Further experiments are needed to elucidate the exact role of these receptors in anxiety. PMID:25620584

Rahimi, Abbasali; Hajizadeh Moghaddam, Akbar; Roohbakhsh, Ali

2015-04-01

235

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

PubMed

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

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

236

GR 38032F (Ondansetron), a selective 5HT 3 receptor antagonist, slows colonic transit in healthy man  

Microsoft Academic Search

The newly recognized class of 5-hydroxytryptamine receptors (5HT3) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT3 receptors are present on enteric neurons, and 5HT3 blockers may produce mild constipation; we thus hypothesized that 5HT3 receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT3 antagonist

N. J. Talley; S. F. Phillips; A. Haddad; L. J. Miller; C. Twomey; A. R. Zinsmeister; R. L. MacCarty; A. Ciociola

1990-01-01

237

Blonanserin, an antipsychotic and dopamine D?/D?receptor antagonist, and ameliorated alcohol dependence.  

PubMed

Blonanserin (BNS) is used for treatment of both positive and negative symptoms of schizophrenia in Japan and Korea. Because BNS has weak ?1 receptor blocking activities and is almost devoid of histamine H1 and muscarinic M1 antagonist activity, BNS is better tolerated than other atypical antipsychotics. A high degree of D? receptor blockage is reported to be predictive of drug abuse and alcoholism, and BNS has strong D? receptor antagonism. Thus, BNS may be useful in the treatment of alcoholism. We present a case in which BNS ameliorated alcohol dependence. PMID:23503552

Takaki, Manabu; Ujike, Hiroshi

2013-01-01

238

Effects of Selective and Non-Selective Glucocorticoid Receptor II Antagonists on Rapid-Onset Diabetes in Young Rats  

PubMed Central

The blockade of glucocorticoid (GC) action through antagonism of the glucocorticoid receptor II (GRII) has been used to minimize the undesirable effects of chronically elevated GC levels. Mifepristone (RU486) is known to competitively block GRII action, but not exclusively, as it antagonizes the progesterone receptor. A number of new selective GRII antagonists have been developed, but limited testing has been completed in animal models of overt type 2 diabetes mellitus. Therefore, two selective GRII antagonists (C113176 and C108297) were tested to determine their effects in our model of GC-induced rapid-onset diabetes (ROD). Male Sprague-Dawley rats (? six weeks of age) were placed on a high-fat diet (60%), surgically implanted with pellets containing corticosterone (CORT) or wax (control) and divided into five treatment groups. Each group was treated with either a GRII antagonist or vehicle for 14 days after surgery: CORT pellets (400 mg/rat) + antagonists (80 mg/kg/day); CORT pellets + drug vehicle; and wax pellets (control) + drug vehicle. After 10 days of CORT treatment, body mass gain was increased with RU486 (by ?20% from baseline) and maintained with C113176 administration, whereas rats given C108297 had similar body mass loss (?15%) to ROD animals. Fasting glycemia was elevated in the ROD animals (>20 mM), normalized completely in animals treated with RU486 (6.2±0.1 mM, p<0.05) and improved in animals treated with C108297 and C113176 (14.0±1.6 and 8.8±1.6 mM, p<0.05 respectively). Glucose intolerance was normalized with RU486 treatment, whereas acute insulin response was improved with RU486 and C113176 treatment. Also, peripheral insulin resistance was attenuated with C113176 treatment along with improved levels of ?-cell function while C108297 antagonism only provided modest improvements. In summary, C113176 is an effective agent that minimized some GC-induced detrimental metabolic effects and may provide an alternative to the effective, but non-selective, GRII antagonist RU486. PMID:24642683

Beaudry, Jacqueline L.; Dunford, Emily C.; Teich, Trevor; Zaharieva, Dessi; Hunt, Hazel; Belanoff, Joseph K.; Riddell, Michael C.

2014-01-01

239

Chemokine receptors and their antagonists in allergic lung disease  

Microsoft Academic Search

The trafficking and homing of leukocytes in normal homeostasis and in disease is under the control of a variety of cytokine and lipid mediators. One family of small cytokines particularly involved in inflammation which has been identified is the chemokine family. Their action is mediated by a large superfamily of seven transmembrane spanning G-protein coupled receptors. One of the hopes

T. N. C. Wells; A. E. I. Proudfoot

1999-01-01

240

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

PubMed

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

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

1995-01-01

241

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

PubMed Central

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

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

242

Inhibition of human and mouse plasma membrane bound NTPDases by P2 receptor antagonists.  

PubMed

The plasma membrane bound nucleoside triphosphate diphosphohydrolase (NTPDase)-1, 2, 3 and 8 are major ectonucleotidases that modulate P2 receptor signaling by controlling nucleotides' concentrations at the cell surface. In this report, we systematically evaluated the effect of the commonly used P2 receptor antagonists reactive blue 2, suramin, NF279, NF449 and MRS2179, on recombinant human and mouse NTPDase1, 2, 3 and 8. Enzymatic reactions were performed in a Tris/calcium buffer, commonly used to evaluate NTPDase activity, and in a more physiological Ringer modified buffer. Although there were some minor variations, there were no major changes either in the enzymatic activity or in the profile of NTPDase inhibition between the two buffers. Except for MRS2179, all other antagonists significantly inhibited these ecto-ATPases; NTPDase3 being the most sensitive to inhibition and NTPDase8 the most resistant. Estimated IC(50) showed that human NTPDases were generally more sensitive to the P2 receptor antagonists tested than the corresponding mouse isoforms. NF279 and reactive blue 2 were the most potent inhibitors of NTPDases which almost completely abrogated their activity at the concentration of 100 microM. In conclusion, reactive blue 2, suramin, NF279 and NF449, at the concentrations commonly used to antagonize P2 receptors, inhibit the four major ecto-ATPases. This information may reveal useful for the interpretation of some pharmacological studies of P2 receptors. In addition, NF279 is a most potent non-selective NTPDase inhibitor. Although P2 receptor antagonists do not display a strict selectivity toward NTPDases, their IC(50) values may help to discriminate some of these enzymes. PMID:17727821

Munkonda, Mercedes N; Kauffenstein, Gilles; Kukulski, Filip; Lévesque, Sébastien A; Legendre, Charlčne; Pelletier, Julie; Lavoie, Elise G; Lecka, Joanna; Sévigny, Jean

2007-11-15

243

Antagonistic Rgg Regulators Mediate Quorum Sensing via Competitive DNA Binding in Streptococcus pyogenes  

PubMed Central

ABSTRACT Recent studies have established the fact that multiple members of the Rgg family of transcriptional regulators serve as key components of quorum sensing (QS) pathways that utilize peptides as intercellular signaling molecules. We previously described a novel QS system in Streptococcus pyogenes which utilizes two Rgg-family regulators (Rgg2 and Rgg3) that respond to neighboring signaling peptides (SHP2 and SHP3) to control gene expression and biofilm formation. We have shown that Rgg2 is a transcriptional activator of target genes, whereas Rgg3 represses expression of these genes, and that SHPs function to activate the QS system. The mechanisms by which Rgg proteins regulate both QS-dependent and QS-independent processes remain poorly defined; thus, we sought to further elucidate how Rgg2 and Rgg3 mediate gene regulation. Here we provide evidence that S. pyogenes employs a unique mechanism of direct competition between the antagonistic, peptide-responsive proteins Rgg2 and Rgg3 for binding at target promoters. The highly conserved, shared binding sites for Rgg2 and Rgg3 are located proximal to the ?35 nucleotide in the target promoters, and the direct competition between the two regulators results in concentration-dependent, exclusive occupation of the target promoters that can be skewed in favor of Rgg2 in vitro by the presence of SHP. These results suggest that exclusionary binding of target promoters by Rgg3 may prevent Rgg2 binding under SHP-limiting conditions, thereby preventing premature induction of the quorum sensing circuit. PMID:23188510

LaSarre, Breah; Aggarwal, Chaitanya; Federle, Michael J.

2012-01-01

244

Antimyoclonic properties of S2 serotonin receptor antagonists in the rat.  

PubMed

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus. PMID:2936977

Pranzatelli, M R; Snodgrass, S R

1986-01-01

245

Synthesis and evaluation of 11?-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists  

PubMed Central

Introduction As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11?-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11?-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11?-aryl estradiol analogs or their potential as scaffolds for drug conjugation. Methods We prepared and characterized a series of 11?-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ER?-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists. Results The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ER?-LBD, ranging from 13–83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11?-substituent than upon the nature of the terminal group Conclusions We have developed a synthetic strategy that provides facile access to potent 11?-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER?-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11?-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11?-aryl estradiol analogs as potential drug delivery systems and imaging agents. PMID:22608920

Hanson, Robert N.; Hua, Edward; Hendricks, J. Adam; Labaree, David; Hochberg, Richard B.

2012-01-01

246

Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.  

PubMed

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling. PMID:24166413

Opal, M D; Klenotich, S C; Morais, M; Bessa, J; Winkle, J; Doukas, D; Kay, L J; Sousa, N; Dulawa, S M

2014-10-01

247

Discovery and development of orexin receptor antagonists as therapeutics for insomnia  

PubMed Central

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. Linked ArticlesThis article is part of a themed section on Orexin Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-2 PMID:23731216

Winrow, CJ; Renger, JJ

2014-01-01

248

Mechanisms of Estrogen Receptor-Mediated Agonistic and Antagonistic Effects  

Microsoft Academic Search

Estrogenic compounds exert a vast variety of effects in wildlife and humans. Endogenous estrogens, like estradiol, regulate\\u000a growth and development of their target tissues. Exogenous compounds with estrogenic and\\/or anti-estrogenic activities may\\u000a disrupt these regulatory pathways. Environmental or industrial chemicals and phytoestrogens interfering with the hormonal\\u000a or endocrine system are defined as endocrine disruptor. The estrogen receptor is the major

Stefan O. Mueller; Kenneth S. Korach

249

GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster  

PubMed Central

The present study investigated the inhibitory effect of losartan, a type 1 angiotensin II receptor (AT1) antagonist, and of combined treatment with losartan and GR144053, a fibrinogen receptor (GPIIb/IIIa) antagonist, on neointima formation subsequent to vascular injury in the hamster carotid artery. Vascular injury was achieved by a roughened-tip 2F catheter and the neointimal area was measured up to 2 weeeks inducing the injury. Compared to non-treated hamsters (intimal area (IA)/internal elastic laminal area (IELA) ratio = 60.3±5.9%, n=12), losartan dissolved in drinking water (1, 3 and 10?mg?kg?1 per day, n=8 each) reduced neointimal area dose-dependently, a significant decrease (IA/IELA=39.7±5.6%) being attained with the highest dose when it was administered from 1 day before injury. However, neointima formation was not prevented even with the highest dose of losartan when the administration was started after injury. When the administration of GR144053 (1.0?mg?kg?1 per hour) via an implanted osmotic pump was started 30?min before the injury and continued for the next 2 weeks, no suppression of neointima formation was observed, although platelet aggregation evoked ex vivo by adenosine diphosphate (ADP) at the end of treatment period was efficiently inhibited. In separate experiments in which 5-bromo-2-deoxy-Uridine (BrdU) was used to test smooth muscle cell (SMC) proliferation 1 and 7 days after injury, the ratio of SMC proliferation in the injured area was only slightly decreased by losartan when its administration was started after the injury, despite the marked reduction of SMC proliferation when treatment was started before the injury. Treatment with GR144053 as indicated above also significantly decreased the SMC proliferating index 1 day after the injury. To examine the potential benefit of the coadministration of the GPIIb/IIIa antagonist with the AT1 receptor antagonist, GR144053 (1.0?mg?kg?1 per hour) was combined with post-injury treatment with losartan (10?mg?kg?1 per day). This markedly reduced the proliferation of SMCs and significantly decreased the neointimal area (IA/IELA=31.2±4.6%) measured 2 weeks following the catheterization. According to the results of a time-dependent study in which GR144053 was given in combination with post injury treatment with losartan for 1, 3, 7 or 14 days, neointima formation could be reduced by treatment with GR144053 for just 7 days. In conclusion, GR144053, a fibrinogen receptor antagonist, enhanced the inhibitory effect of losartan, an AT1 receptor antagonist, on neointima formation in the damaged carotid artery of hamsters. PMID:9480031

Matsuno, Hiroyuki; Kozawa, Osamu; Niwa, Masayuki; Kaida, Takehiro; Hayashi, Hideharu; Uematsu, Toshihiko

1997-01-01

250

Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor.  

PubMed

1. This study characterises the binding of a novel nonpeptide antagonist radioligand, [(3)H]SB-674042 (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone), to the human orexin-1 (OX(1)) receptor stably expressed in Chinese hamster ovary (CHO) cells in both a whole cell assay and in a cell membrane-based scintillation proximity assay (SPA) format. 2. Specific binding of [(3)H]SB-674042 was saturable in both whole cell and membrane formats. Analyses suggested a single high-affinity site, with K(d) values of 3.76+/-0.45 and 5.03+/-0.31 nm, and corresponding B(max) values of 30.8+/-1.8 and 34.4+/-2.0 pmol mg protein(-1), in whole cell and membrane formats, respectively. Kinetic studies yielded similar K(d) values. 3. Competition studies in whole cells revealed that the native orexin peptides display a low affinity for the OX(1) receptor, with orexin-A displaying a approximately five-fold higher affinity than orexin-B (K(i) values of 318+/-158 and 1516+/-597 nm, respectively). 4. SB-334867, SB-408124 (1-(6,8-difluoro-2-methyl-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) and SB-410220 (1-(5,8-difluoro-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) all displayed high affinity for the OX(1) receptor in both whole cell (K(i) values 99+/-18, 57+/-8.3 and 19+/-4.5 nm, respectively) and membrane (K(i) values 38+/-3.6, 27+/-4.1 and 4.5+/-0.2 nm, respectively) formats. 5. Calcium mobilisation studies showed that SB-334867, SB-408124 and SB-410220 are all functional antagonists of the OX(1) receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50-fold selectivity over the orexin-2 receptor. 6. These studies indicate that [(3)H]SB-674042 is a specific, high-affinity radioligand for the OX(1) receptor. The availability of this radioligand will be a valuable tool with which to investigate the physiological functions of OX(1) receptors. PMID:14691055

Langmead, Christopher J; Jerman, Jeffrey C; Brough, Stephen J; Scott, Claire; Porter, Rod A; Herdon, Hugh J

2004-01-01

251

Metabolism studies of ifenprodil, a potent GluN2B receptor antagonist.  

PubMed

The NMDA receptor antagonist ifenprodil is an important lead structure for developing new GluN2B selective NMDA receptor antagonists. Ifenprodil itself has a high affinity to the GluN2B subunit but a poor selectivity for the NMDA receptor. This aspect and the fast biotransformation are the major drawbacks of ifenprodil. In order to optimize the development of new and more selective GluN2B (NMDA) receptor antagonists, the identification of the main metabolic pathways of ifenprodil is necessary. Herein the in vitro and in vivo phase I and phase II metabolites of ifenprodil were generated and analyzed via LC-MS(n) experiments. In vitro experiments were carried out with rat liver microsomes and various co-factors to generate phase I and phase II metabolites. The application of ifenprodil to a rat and the analysis of its urine led to the identification of diverse formed in vivo metabolites. The phenol represents the metabolically most labile structural element since glucuronide 7 and 8 appeared as main metabolites. PMID:24042122

Falck, Evamaria; Begrow, Frank; Verspohl, Eugen; Wünsch, Bernhard

2014-01-01

252

The 5-HT2A Receptor Antagonist M100907 Produces Antiparkinsonian Effects and Decreases Striatal Glutamate  

PubMed Central

5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD). Clinical studies have suggested that 5-HT2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of PD. PMID:21716656

Ansah, Twum A.; Ferguson, Marcus C.; Nayyar, Tultul

2011-01-01

253

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

PubMed Central

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

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

2014-01-01

254

Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible ? Opioid Receptor Antagonist Effects  

PubMed Central

We have previously shown that cinnamoyl derivatives of 14?-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7?-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible ? opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid ?-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of ?-FNA is clearly ? opioid receptor (KOR) mediated. PMID:23043264

2012-01-01

255

The actions of orally active GABAB receptor antagonists on GABAergic transmission in vivo and in vitro.  

PubMed

The goal of this report is to present the results obtained with three new GABAB receptor antagonists. CGP 54062 has an IC50 in a GABAB binding test of 0.013 microM which is roughly 2500-fold lower than one of the most potent blockers known so far, CGP 35348 (IC50 = 34 microM). CGP 46381 and CGP 36742 have IC50s of 4.9 and 36 microM respectively. The latter two compounds are the first orally active GABAB receptor antagonists. All three compounds bind to the GABAB receptor selectively, and are inactive in a number of binding tests assessing the compounds' affinity to various other receptor sites. The effect of these blockers on GABAergic transmission was investigated in the CA1 area of hippocampal slices. The Schaffer collateral/commissural fibers were stimulated and the evoked postsynaptic potentials were recorded intracellularly in pyramidal neurons. The three antagonists blocked the late inhibitory postsynaptic potential with the following rank order of potency CGP 54062 > 46381 > 36742 approximately 35348. These findings support the hypothesis that these potentials are mediated by GABAB receptors. Orally administered CGP 36742 and CGP 46381 block the neuronal depression induced by iontophoretically applied baclofen in anaesthetised rats. Up to a dose of 10 mg/kg i.v. CGP 54062 was inactive and thus does not appear to cross the blood-brain barrier at this dose. In anaesthetised rats the effects of the three new GABAB antagonists and of CGP 35348 were investigated on the paired-pulse inhibition of the population spikes evoked in the CA1 area of the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8385620

Olpe, H R; Steinmann, M W; Ferrat, T; Pozza, M F; Greiner, K; Brugger, F; Froestl, W; Mickel, S J; Bittiger, H

1993-03-23

256

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

PubMed Central

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

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

257

RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists  

PubMed Central

Prostacyclin (PGI2) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794). RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pKi) were 9.3±0.1 and 7.7±0.03, respectively; in a recombinant IP receptor system, pKi values were 8.7±0.06 and 6.9±0.1, respectively. Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pKi) of RO1138452 and RO3244794 were 9.0±0.06 and 8.5±0.11, respectively. Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I2 (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pKi values for EP1 (<5), EP3 (5.38), EP4 (5.74) and TP (5.09). RO1138452 (1–10?mg?kg?1, i.v.) and RO3244794 (1–30?mg?kg?1, i.v.) significantly reduced acetic acid-induced abdominal constrictions. RO1138452 (3–100?mg?kg?1, p.o.) and RO3244794 (0.3–30?mg?kg?1, p.o.) significantly reduced carrageenan-induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10?mg?kg?1, p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti-inflammatory potential. PMID:16331286

Bley, Keith R; Bhattacharya, Anindya; Daniels, Don V; Gever, Joel; Jahangir, Alam; O'Yang, Counde; Smith, Steven; Srinivasan, Dinesh; Ford, Anthony P D W; Jett, Mary-Frances

2005-01-01

258

RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists.  

PubMed

Prostacyclin (PGI2) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794).RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pKi) were 9.3 +/- 0.1 and 7.7 +/- 0.03, respectively; in a recombinant IP receptor system, pKi values were 8.7 +/- 0.06 and 6.9 +/- 0.1, respectively. Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pKi) of RO1138452 and RO3244794 were 9.0 +/- 0.06 and 8.5 +/- 0.11, respectively. Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I2 (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pKi values for EP1 (< 5), EP3 (5.38), EP4 (5.74) and TP (5.09). RO1138452 (1-10 mg kg(-1), i.v.) and RO3244794 (1-30 mg kg(-1), i.v.) significantly reduced acetic acid-induced abdominal constrictions. RO1138452 (3-100 mg kg(-1), p.o.) and RO3244794 (0.3-30 mg kg(-1), p.o.) significantly reduced carrageenan-induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10 mg kg(-1), p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti-inflammatory potential. PMID:16331286

Bley, Keith R; Bhattacharya, Anindya; Daniels, Don V; Gever, Joel; Jahangir, Alam; O'Yang, Counde; Smith, Steven; Srinivasan, Dinesh; Ford, Anthony P D W; Jett, Mary-Frances

2006-02-01

259

Subtype-selective N-methyl-D-aspartate receptor antagonists: benzimidazalone and hydantoin as phenol replacements.  

PubMed

Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally. PMID:10794706

Schelkun, R M; Yuen, P W; Serpa, K; Meltzer, L T; Wise, L D; Whittemore, E R; Woodward, R M

2000-05-01

260

Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action  

SciTech Connect

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 (cis-(+-)-4-((2H-tetrazol-5-yl)methyl)piperidine-2-carboxylic acid), the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of (3H) CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in (3H)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or (3H)kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity.

Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M. (Eli Lilly and Company, Indianapolis, IN (USA))

1990-12-01

261

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors  

PubMed Central

The P2Y1 receptor responds to adenine nucleotides and is present in platelets, heart, smooth muscles prostate, ovary, and brain. A selective antagonist may be useful as an antithrombotic agent. We have analyzed the binding site of this G protein-coupled receptor using ligand design, site-directed mutagenesis, and homology modeling based on rhodopsin. We have designed and synthesized a series of deoxyadenosine 3?,5?-bisphosphate derivatives that act as antagonists, or, in some cases with small structural changes, as agonists or partial agonists. The 2-position accommodates Cl or thioethers, whereas the N6-position is limited to Me or Et. 2?-Substitution with OH or OMe increases agonist efficacy over 2?-H. Using molecular modeling of the binding site, the oxygen atoms of the ribose moiety were predicted to be non-essential, i.e. no specific H-bonds with the receptor protein appear in the model. We have, therefore, substituted this moiety with carbocylics, smaller and larger rings, conformationally constrained rings, and acyclics, with retention of affinity for the receptor. With simplified pharmacophores we are exploring the steric and electronic requirements of the receptor binding site, and the structural basis of receptor activation. PMID:11347970

Jacobson, Kenneth A.; Moro, Stefano; Hoffmann, Carsten; Kim, Yong-Chul; Kim, Hak Sung; Ravi, R. Gnana; Harden, T. Kendall; Boyer, José L.

2015-01-01

262

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist.  

PubMed

In normal physiologic responses to injury and infection, inflammatory cells enter tissue and sites of inflammation through a chemotactic process regulated by several families of proteins, including inflammatory chemokines, a family of small inducible cytokines. In neutrophils, chemokines chemokine (CXC motif) ligand 1 (CXCL1) and CXCL8 are potent chemoattractants and activate G protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXCR2. Several small-molecule antagonists of CXCR2 have been developed to inhibit the inflammatory responses mediated by this receptor. Here, we present the data describing the pharmacology of AZD5069 [N-(2-(2,3-difluorobenzylthio)-6-((2R,3S)-3,4-dihydroxybutan-2-yloxy)[2,4,5,6-(13)C4, 1,3-(15)N2]pyrimidin-4-yl)azetidine-1-sulfonamide,[(15)N2,(13)C4]N-(2-(2,3-difluoro-6-[3H]-benzylthio)-6-((2R,3S)-3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide], a novel antagonist of CXCR2. AZD5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA2 of approximately 9.6, and adhesion molecule expression, with a pA2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. With short incubation times, AZD5069 appeared to have an antagonist profile with insurmountable antagonism of calcium response curves. This behavior was also observed in vivo in an acute lipopolysaccharide-induced lung inflammation model. Altogether, the data presented here show that AZD5069 represents a novel, potent, and selective CXCR2 antagonist with potential as a therapeutic agent in inflammatory conditions. PMID:25736418

Nicholls, David J; Wiley, Katherine; Dainty, Ian; MacIntosh, Fraser; Phillips, Caroline; Gaw, Alasdair; Mĺrdh, Carina Kärrman

2015-05-01

263

MIBE acts as antagonist ligand of both estrogen receptor ? and GPER in breast cancer cells  

PubMed Central

Introduction The multiple biological responses to estrogens are mainly mediated by the classical estrogen receptors ER? and ER?, which act as ligand-activated transcription factors. ER? exerts a main role in the development of breast cancer; therefore, the ER antagonist tamoxifen has been widely used although its effectiveness is limited by de novo and acquired resistance. Recently, GPR30/GPER, a member of the seven-transmembrane G protein-coupled receptor family, has been implicated in mediating the effects of estrogens in various normal and cancer cells. In particular, GPER triggered gene expression and proliferative responses induced by estrogens and even ER antagonists in hormone-sensitive tumor cells. Likewise, additional ER ligands showed the ability to bind to GPER eliciting promiscuous and, in some cases, opposite actions through the two receptors. We synthesized a novel compound (ethyl 3-[5-(2-ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]but-2-enoate), referred to as MIBE, and investigated its properties elicited through ER? and GPER in breast cancer cells. Methods Molecular modeling, binding experiments and functional assays were performed in order to evaluate the biological action exerted by MIBE through ER? and GPER in MCF7 and SkBr3 breast cancer cells. Results MIBE displayed the ability to act as an antagonist ligand for ER? and GPER as it elicited inhibitory effects on gene transcription and growth effects by binding to both receptors in breast cancer cells. Moreover, GPER was required for epidermal growth factor receptor (EGFR) and ERK activation by EGF as ascertained by using MIBE and performing gene silencing experiments. Conclusions Our findings provide novel insights on the functional cross-talk between GPER and EGFR signaling. Furthermore, the exclusive antagonistic activity exerted by MIBE on ER? and GPER could represent an innovative pharmacological approach targeting breast carcinomas which express one or both receptors at the beginning and/or during tumor progression. Hence, the simultaneous inhibition of both ER? and GPER may guarantee major therapeutic benefits in respect to the use of a selective estrogen receptor antagonist. PMID:22251451

2012-01-01

264

Amantadine, a N-Methyl-d-Aspartate Receptor Antagonist, Does Not Enhance Postoperative Analgesia in Women Undergoing Abdominal Hysterectomy  

Microsoft Academic Search

N-methyl-d-aspartate (NMDA) antagonists adminis- tered before surgery will improve postoperative anal- gesia, presumably by inhibiting spinal sensitization processes. However, current clinical formulations of NMDA antagonists either enable only an oral applica- tion (i.e., dextromethorphan) or are associated with psychotropic side effects, as with the IV delivery of ket- amine. Because of its noncompetitive NMDA receptor antagonist characteristics, amantadine may improve

Frank Schroeder; Mike Ufer; Hartmut Buerkle; Thomas Standl

2001-01-01

265

Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist barusiban in comparison to the agonists oxytocin and carbetocin.  

PubMed

We have analyzed binding domains of the oxytocin receptor for barusiban, a highly selective oxytocin receptor antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the oxytocin receptor. PMID:15740719

Gimpl, Gerald; Postina, Rolf; Fahrenholz, Falk; Reinheimer, Torsten

2005-03-01

266

Interaction of new, very potent non-nucleotide antagonists with Arg256 of the human platelet P2Y12 receptor.  

PubMed

The P2Y(12) receptor plays a crucial role in platelet aggregation. In the present study, we analyzed the properties of non-nucleotide antagonists at the recombinant human P2Y(12) receptor and searched for amino acids involved in the molecular interaction. Receptor function was assessed by measuring the cAMP response element (CRE)-directed luciferase expression in Chinese hamster ovary cells. The cellular cAMP production was accelerated by forskolin; 2-methylthio-ADP was used to activate the wild-type P2Y(12) receptor or mutant constructs. 2-Methylthio-ADP inhibited the CRE-dependent luciferase expression with an IC(50) value of approximately 1 nM. The anthraquinone derivative reactive blue 2 used at increasing concentrations shifted the concentration-response curve of 2-methylthio-ADP to the right in a manner compatible with competitive antagonism (pA(2) value, 7.4). Its analog, 1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-0739), showed a markedly higher antagonistic potency with a pA(2) value of 9.8. In cells expressing the R256A-mutant receptor, the potencies of both reactive blue 2 (apparent pK(B), 5.9) and PSB-0739 (apparent pK(B), 9.1) were decreased. The same was true for the pure reactive blue 2 meta- and para-isomers and for the ortho-isomer cibacron blue 3GA. In contrast, the analog, 1-amino-4-[4-anilino-phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, lacking a sulfonic acid residue at ring D (PSB-0826), showed similar pK(B) values at wild-type (8.4) and R256A-mutant receptors (8.3). In summary, the results demonstrate that PSB-0739 is the most potent competitive non-nucleotide antagonist at the human P2Y(12) receptor described so far. The results also indicate that the sulfonic acid residue at ring D is involved in the interaction of antagonists derived from reactive blue 2 with the residue Arg256 of the human P2Y(12) receptor. PMID:19690189

Hoffmann, Kristina; Baqi, Younis; Morena, María Sol; Glänzel, Markus; Müller, Christa E; von Kügelgen, Ivar

2009-11-01

267

Helokinestatin: a new bradykinin B2 receptor antagonist decapeptide from lizard venom.  

PubMed

Synthetic bradykinin antagonist peptides/peptoids have been powerful tools for delineating the roles of kinins in both normal physiology and in pathological states. Here, we report the identification of a novel, naturally occurring bradykinin B2 receptor antagonist peptide, helokinestatin, isolated and structurally characterized from the venoms of helodermatid lizards-the Gila monster (Heloderma suspectum) and the Mexican beaded lizard (Heloderma horridum). The primary structure of the peptide was established by a combination of microsequencing and mass spectroscopy as Gly-Pro-Pro-Tyr-Gln-Pro-Leu-Val-Pro-Arg (Mr 1122.62). A synthetic replicate of helokinestatin was found to inhibit bradykinin-induced vasorelaxation of phenylephrine pre-constricted rat tail artery smooth muscle, mediated by the B2 receptor sub-type, in a dose-dependent manner. Natural selection, that generates functional optimization of predatory reptile venom peptides, can potentially provide new insights for drug lead design or for normal physiological or pathophysiological processes. PMID:18078686

Kwok, Hang Fai; Chen, Tianbao; O'Rourke, Martin; Ivanyi, Craig; Hirst, David; Shaw, Chris

2008-01-01

268

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

PubMed Central

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

2011-01-01

269

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

PubMed

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

Christopher, John A; Congreve, Miles S

2013-02-01

270

[The safety of interleukin-1 receptor antagonist (anakinra) in the treatment of rheumatoid arthritis].  

PubMed

The safety profile of interleukin-1 receptor antagonist (anakinra) has been studied with randomised, placebo-controlled trials involving 2932 patients affected by rheumatoid arthritis. The most frequently reported adverse events were represented by injection site reactions (71%) and headache (13.6%). No statistically significant difference in the incidence of infections was observed among the patients treated with the interleukin-1 receptor antagonist and the patients receiving placebo. In particular, the incidence of serious infections was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in patients on placebo. The reported serious infections consisted of pneumonia, cellulitis, bone and joint infections, bursitis. No case of opportunistic infections or tubercolosis was observed. The results of clinical studies suggest that anakinra is a new well-tolerated drug for the treatment of patients affected by rheumatoid arthritis. PMID:15201943

Riente, L

2004-01-01

271

Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists  

PubMed Central

As a part of our program to develop OX1-CB1 bivalent ligands, we required a better understanding of the basic structure-activity relationships (SARs) of orexin antagonists. A series of SB-334867 analogues were synthesized and evaluated in calcium mobilization assays. SAR results suggest that the 2-methylbenzoxazole moiety may be replaced with a disubstituted 4-aminophenyl group without loss of activity and an electron-deficient system is generally preferred at the 1,5-naphthyridine moiety for OX1 antagonist activity. In particular, substitution of larger potential linkers such as n-hexyl provided compound 33 with equivalent activity at the OX1 receptor compared to the lead compound SB-334867. These compounds should be of value in the development of ligands targeting the orexin-1 receptor and its potential heterodimers. PMID:21478014

Perrey, David A.; Gilmour, Brian P.; Runyon, Scott P.; Thomas, Brian F.; Zhang, Yanan

2011-01-01

272

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

PubMed Central

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

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

1994-01-01

273

Effect of 5HT 3 receptor antagonists on the discriminative stimulus properties of morphine in rats  

Microsoft Academic Search

5-HT3 receptor antagonists, e.g. MDL72222, ondansetron and ICS205-930, have been previously reported to block a morphine (1.5 mg\\/kg)-induced conditioned place preference in rats. This finding suggests that these drugs may modify the morphine discriminative stimulus which underlies place conditioning. To study this further we have examined the effects of MDL72222, ondansetron and ICS205-930 against a morphine discriminative stimulus using a

Narges Joharchi; Edward M. Sellers; Guy A. Higgins

1993-01-01

274

Effects of 5HT 3 receptor antagonists on behavioural measures of naloxone-precipitated opioid withdrawal  

Microsoft Academic Search

The effect of the selective 5-HT3 receptor antagonists, ondansetron and MDL 72222, against various behaviours elicited by naloxone-precipitated morphine withdrawal were examined. Rats made dependent upon morphine by the subcutaneous implantation of a 75 mg pellet, when challenged with naloxone (0.5 mg\\/kg SC), 3 or 4 days later exhibited a wide range of behaviours including wet dog shakes, paw shakes,

Guy A. Higgins; Peter Nguyen; Narges Joharchi; Edward M. Sellers

1991-01-01

275

The angiotensin II receptor antagonist candesartan cilexetil (TCV-116) ameliorates retinal disorders in rats  

Microsoft Academic Search

Aims\\/hypothesis. The results of the EUCLID trial (EURODIAB Controlled Trial of Lisinopril in Insulin-dependent Diabetes Mellitus) highlighted\\u000a the importance of the renin-angiotensin system in the pathogenesis of diabetic retinopathy. Candesartan cilexetil (TCV-116),\\u000a a potent angiotensin II (AII) receptor antagonist, has beneficial effects on hypertension as well as on heart, renal and cerebrovascular\\u000a disease. We aimed to evaluate the effectiveness of

Y. Nagisa; A. Shintani; S. Nakagawa

2001-01-01

276

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

PubMed Central

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

Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgĺrd, 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

277

Benzimidazole-2-carboxamides as novel NR2B selective NMDA receptor antagonists.  

PubMed

A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration. PMID:16782335

Borza, István; Kolok, Sándor; Gere, Anikó; Nagy, József; Fodor, László; Galgóczy, Kornél; Fetter, József; Bertha, Ferenc; Agai, Béla; Horváth, Csilla; Farkas, Sándor; Domány, György

2006-09-01

278

Evidence of a pharmacogenomic response to interleukin-l receptor antagonist in rheumatoid arthritis  

Microsoft Academic Search

Biological activity of the IL-1 system depends on the balance between two proinflammatory proteins (IL-1? and IL-1?) and the related anti-inflammatory protein, the IL-1 receptor antagonist (IL-1Ra). The genes for these proteins lie within 430 kb on human chromosome 2. Based on a clinical trial of human recombinant IL-1ra in rheumatoid arthritis, we tested whether IL-1 genotype might be related

N J Camp; A Cox; F S di Giovine; D McCabe; W Rich; G W Duff

2005-01-01

279

Haemodynamic effects of endothelin receptor antagonist, tezosentan, in tumour necrosis factor-a treated anaesthetized rats  

Microsoft Academic Search

Administration of tumour necrosis factor-f (TNF-f) produces progressive reduction in cardiac output (CO) by affecting preload, afterload and cardiac contractility. We have examined the effect of an endothelin receptor antagonist, tezosentan (1, 3 or 10 mg\\/kg), on CO, heart rate (HR), blood pressure (BP), mean circulatory filling pressure (Pmcf), resistance to venous return (RVR), arterial resistance (AR), dP\\/dt, stroke volume

Reza Tabrizchi; Carol Ann Ford

2003-01-01

280

Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist  

Microsoft Academic Search

Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted

Beth Borowsky; Margaret M. Durkin; Kristine Ogozalek; Mohammad R. Marzabadi; John DeLeon; Rainer Heurich; Harvey Lichtblau; Zoya Shaposhnik; Irena Daniewska; Thomas P. Blackburn; Theresa A. Branchek; Christophe Gerald; Pierre J. Vaysse; Carlos Forray

2002-01-01

281

NO in Exhaled Air of Asthmatic Children Is Reduced by the Leukotriene Receptor Antagonist Montelukast  

Microsoft Academic Search

Nitric oxide in exhaled air (F ENO ) is increased in asthmatic children, probably reflecting aspects of air- way inflammation. We have studied the effect of the leukotriene receptor antagonist (LTRA) mon- telukast on F ENO with a view to elucidate potential anti-inflammatory properties of LTRAs. Twenty-six asthmatic children 6 to 15 yr of age completed a double-blind crossover trial

HANS BISGAARD; LOTTE LOLAND; JACOB ANHŘJ

1999-01-01

282

A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene–receptor antagonist  

Microsoft Academic Search

Background: The cysteinyl leukotrienes are important mediators of bronchial asthma. The clinical effect of montelukast, a potent cysteinyl leukotriene–receptor antagonist, was investigated in a randomized, placebo-controlled, multicenter, parallel-group, dose-ranging study.Methods: After a 3-week, single-blind, placebo run-in period, 343 asthmatic patients (FEV1 40% to 80% of the predicted value with an improvement in FEV1 of at least 15% [absolute value] after

Leonard C. Altman; Zev Munk; James Seltzer; Nancy Noonan; Sumiko Shingo; Ji Zhang; Theodore F. Reiss

1998-01-01

283

Histamine H1 and H2 Receptor Antagonists Accelerate Skin Barrier Repair and Prevent Epidermal Hyperplasia Induced by Barrier Disruption in a Dry Environment  

Microsoft Academic Search

Keratinocytes have histamine H1 and H2 receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H2 receptor antagonists famotidine and cimetidine accelerated the recovery of

Yutaka Ashida; Mitsuhiro Denda; Tetsuji Hirao

2001-01-01

284

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

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.

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

285

Brain Penetration and In Vivo Recovery of NMDA Receptor Antagonists Amantadine and Memantine: A Quantitative Microdialysis Study  

Microsoft Academic Search

Purpose. To determine free brain concentrations of the clinically used uncompetitive NMDA antagonists memantine and amantadine using microdialysis corrected for in vivo recovery in relations to serum, CSF and brain tissue levels and their in vitro potency at NMDA receptors.

Mayke B. Hesselink; Bert G. De Boer; Douwe D. Breimer; Wojciech Danysz

1999-01-01

286

Role of Vasopressin and Vasopressin Receptor Antagonists in Type I Cardiorenal Syndrome  

PubMed Central

The pathogenesis of cardiac failure involves activation of the neurohumoral axis including stimulation of the sympathetic nervous system, the renin-angiotensin-aldosterone, and nonosmotic vasopressin systems. While these responses are critical in maintaining arterial pressure, they are associated with renal vasoconstriction, as well as sodium and water retention. In advanced circumstances, renal dysfunction and hyponatremia occur with cardiac failure. Even a modest rise in serum creatinine related to diminished renal function in heart failure patients is associated with increased risk for cardiovascular morbidity and mortality. Similarly, increased thirst and the nonosmotic stimulation of vasopressin in advanced cardiac failure leads to hyponatremia, which is also a major risk factor for mortality. Currently, V2 vasopressin receptor antagonists have been shown to correct hyponatremia in cardiac failure. One such agent, conivaptan, also is a V1 receptor antagonist which could theoretically benefit heart failure patients by decreasing cardiac afterload and remodeling. The effect of V2 receptor antagonists to correct hyponatremia in heart failure patients appears to be quite safe. However, to date no effect on mortality has been demonstrated. PMID:19169014

Schrier, Robert W.; Masoumi, Amirali; Elhassan, Elwaleed

2009-01-01

287

Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2.  

PubMed

P2 membrane receptors for nucleotides represent significant targets for experimental pharmacology and drug research. In earlier publications, we have shown that Reactive Blue 2 (RB 2), one of the most widely used P2-receptor antagonists, displays only moderate affinity and does not discriminate between native P2X- and P2Y-receptor subtypes. In the present study we have pharmacologically evaluated a series of 15 synthesized and re-evaluated four commercially obtained and chromatographically purified RB 2 type anthraquinone derivatives on contractions of the rat vas deferens (RVD) elicited by alpha,beta-methylene ATP (alpha,beta-meATP), mediated by P2X1-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS), mediated by P2Y1-like receptors. Based on the structure-activity relationships (SAR) it is concluded that hydrophobic interactions of aromatic pi-electron systems, hydrogen bonds with nitrogen as donor and acceptor atoms, and, particularly, position, conformational distance and number of anionic sulfonate groups are of great importance for the blockade of the two native P2-receptor subtypes. We have also identified novel, for the most part reversible antagonists that bind with higher affinity and improved subtype selectivity in comparison to RB 2. In particular, 1-amino-4-{4-[4-chloro-6-(2-sulfonatophenylamino)-[1,3,5]triazine-2-ylamino]-2-sulfonatophenylamino}-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid trisodium salt (MG 50-3-1) is the most potent antagonist at the P2Y1-like-receptors of the GPTC reported so far (IC50=4.6 nM). It is significantly less potent as reversible antagonist at the P2X1-receptors of the RVD (IC50=2.8 microM). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations. PMID:16153748

Glänzel, Markus; Bültmann, Ralph; Starke, Klaus; Frahm, August W

2005-12-01

288

Evidence that 5-HT2c receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety.  

PubMed

Four non-selective 5-HT2C/5-HT2A receptor antagonists, mianserin (2-8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5-1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT2A receptor antagonists ketanserin (0.2-1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT1A, 5-HT1B and beta-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT1D receptor partial agonist and alpha 2 adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H1 receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT2C/5-HT2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT2C/5-HT2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT2C receptor, although the possibility of 5-HT2B receptor mediation is discussed. PMID:7846211

Kennett, G A; Pittaway, K; Blackburn, T P

1994-02-01

289

Characterization of angiotensin II antagonism displayed by Ib, a novel nonpeptide angiotensin AT(1) receptor antagonist.  

PubMed

The pharmacologic profile of Ib, 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one, a novel nonpeptide angiotensin AT(1) receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in rats. Ib inhibited [(125)I] angiotensin II binding to AT(1) receptors in rat liver membranes (K(i)=2.5+/-0.5 nM) and did not interact with AT(2) receptors in bovine cerebellar membranes. In functional studies with rat and rabbit aorta, Ib inhibited the contractile response to angiotensin II (pD(2)' value: 7.43 and 7.29, respectively) with a significant reduction in the maximum. In pithed rats, Ib inhibited the angiotensin II induced pressor response in a dose-related manner. After intravenous administration, Ib produced a dose-dependent antihypertensive effects in spontaneously hypertensive rats and renal hypertensive rats. These results suggest that Ib is a potent angiotensin AT(1) selective receptor antagonist with a mode of insurmountable antagonism. PMID:18571160

Wu, Jinhui; Wang, Qiujuan; Guo, Jiyuan; Hu, Zheyi; Yin, Zhiyong; Xu, Jinyi; Wu, Xiaoming

2008-07-28

290

Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant.  

PubMed

Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class. PMID:25577040

Raheem, Izzat T; Breslin, Michael J; Bruno, Joseph; Cabalu, Tamara D; Cooke, Andrew; Cox, Christopher D; Cui, Donghui; Garson, Susan; Gotter, Anthony L; Fox, Steven V; Harrell, C Meacham; Kuduk, Scott D; Lemaire, Wei; Prueksaritanont, Thomayant; Renger, John J; Stump, Craig; Tannenbaum, Pamela L; Williams, Peter D; Winrow, Christopher J; Coleman, Paul J

2015-02-01

291

Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus  

PubMed Central

Refractory status epilepticus (RSE) and superrefractory status epilepticus (SRSE) pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA) receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE. PMID:25649724

Zeiler, F. A.

2015-01-01

292

Different antagonist binding properties of rat pancreatic and cardiac muscarinic receptors  

SciTech Connect

The antagonist binding properties of rat pancreatic and cardiac muscarinic receptors were compared. In both tissues pirenzepine (PZ) had a low affinity for muscarinic receptors labelled by (/sup 3/H)N-methylscopolamine ((/sup 3/)NMS) (K/sub D/ values of 140 and 280nM, respectively, in pancreatic and cardiac homogenates). The binding properties of pancreatic and cardiac receptors were, however, markedly different. This was indicated by different affinities for dicyclomine, (11-(/(2-((diethylamino)-methyl)-1-piperidinyl/acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1,4) benzodiazepin-6-on)(AFDX-116), 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP) and hexahydrosiladifenidol (HHSiD). Pancreatic and cardiac muscarinic receptros also showed different (/sup 3/H)NMS association and dissociation rates. These results support the concept of M2 receptor subtypes have different binding kinetic properties. 20 references, 3 figures, 1 table.

Waelbroeck, M.; Camus, J.; Winand, J.; Christophe, J.

1987-11-09

293

Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction  

PubMed Central

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

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

2011-01-01

294

Dopamine Receptors Antagonistically Regulate Behavioral Choice between Conflicting Alternatives in C. elegans  

PubMed Central

Caenorhabditis elegans is a useful model to study the neuronal or molecular basis for behavioral choice, a specific form of decision-making. Although it has been implied that both D1-like and D2-like dopamine receptors may contribute to the control of decision-making in mammals, the genetic interactions between D1-like and D2-like dopamine receptors in regulating decision-making are still largely unclear. In the present study, we investigated the molecular control of behavioral choice between conflicting alternatives (diacetyl and Cu2+) by D1-like and D2-like dopamine receptors and their possible genetic interactions with C. elegans as the assay system. In the behavioral choice assay system, mutation of dop-1 gene encoding D1-like dopamine receptor resulted in the enhanced tendency to cross the Cu2+ barrier compared with wild-type. In contrast, mutations of dop-2 or dop-3 gene encoding D2-like dopamine receptor caused the weak tendency to cross the Cu2+ barrier compared with wild-type. During the control of behavioral choice, DOP-3 antagonistically regulated the function of DOP-1. The behavioral choice phenotype of dop-2; dop-1dop-3 triple mutant further confirmed the possible antagonistic function of D2-like dopamine receptor on D1-like dopamine receptor in regulating behavioral choice. The genetic assays further demonstrate that DOP-3 might act through G?o signaling pathway encoded by GOA-1 and EGL-10, and DOP-1 might act through G?q signaling pathway encoded by EGL-30 and EAT-16 to regulate the behavioral choice. DOP-1 might function in cholinergic neurons to regulate the behavioral choice, whereas DOP-3 might function in GABAergic neurons, RIC, and SIA neurons to regulate the behavioral choice. In this study, we provide the genetic evidence to indicate the antagonistic relationship between D1-like dopamine receptor and D2-like dopamine receptor in regulating the decision-making of animals. Our data will be useful for understanding the complex functions of dopamine receptors in regulating decision-making in animals. PMID:25536037

Wang, Daoyong; Yu, Yonglin; Li, Yinxia; Wang, Yang; Wang, Dayong

2014-01-01

295

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

PubMed

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

Muńoz, Miguel; Berger, Michael; Rosso, Marisa; Gonzalez-Ortega, Ana; Carranza, Andrés; Coveńas, Rafael

2014-01-01

296

The utility of ionotropic glutamate receptor antagonists in the treatment of nociception induced by epidural glutamate infusion in rats  

PubMed Central

Background: The authors have previously demonstrated that human herniated disc material contains high concentrations of free glutamate. In an experimental model, elevated epidural glutamate concentrations in the lumbar spine can cause a focal hyperesthetic state. Methods: Rats underwent epidural glutamate infusion in the lumbar spine by a miniosmotic pump over a 72-hour period. Some rats underwent coinfusion with glutamate and ionotropic glutamate antagonists. Nociception was assessed by von Frey fibers and by assessment of glutamate receptor expression in the corresponding dorsal horn of the spinal cord. Results: The kainic acid antagonist, UBP 301, decreased epidural glutamate-based hyperesthesia in a dose dependent manner. Concordant with these findings, there was significant decrease in kainate receptor expression in the dorsal horn. The N-Methyl-4-isoxazoleproionic acid (NMDA) antagonist Norketamine also significantly diminished hyperesthesia and decreased receptor expression in the dorsal horn. Conclusions: Both UBP 301, the kainic acid receptor antagonist and Norketamine, an NMDA receptor antagonist, dampened epidural glutamate-based nociception. Focal epidural injections of Kainate or NMDA receptor antagonists could be effective treatments for disc herniation-based lumbar radiculopathy. PMID:24032081

Osgood, Doreen P.; Harrington, William F.; Kenney, Elizabeth V.; Harrington, J. Frederick

2013-01-01

297

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

PubMed Central

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

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

2009-01-01

298

Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.  

PubMed

Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review. PMID:24747288

Sharma, Mayank Kumar; Murumkar, Prashant R; Kanhed, Ashish M; Giridhar, Rajani; Yadav, Mange Ram

2014-05-22

299

Fluorescent agonists and antagonists for vasopressin/oxytocin G protein-coupled receptors : usefulness in ligand screening assays and receptor studies.  

E-print Network

1 Fluorescent agonists and antagonists for vasopressin/oxytocin G protein-coupled receptors-vasopressin and oxytocin G protein-coupled receptors. Both cyclic and linear peptide analogs of the neurohypophysial. Keywords : arginine-vasopressin, oxytocin, G protein-coupled receptor, structure-activity relationships

Paris-Sud XI, Université de

300

Investigation of the prostacyclin (IP) receptor antagonist RO1138452 on isolated blood vessel and platelet preparations  

PubMed Central

Background and purpose: The current study examined the utility of the recently described prostacyclin (prostanoid IP) receptor antagonist RO1138452 (2-(4-(4-isopropoxybenzyl)-phenylamino) imidazoline) as a tool for classifying prostanoid receptors. Experimental approach: pA2 values were determined on isolated smooth muscle and platelet preparations. Key results: RO1138452 antagonized relaxation of human pulmonary artery, guinea-pig aorta and rabbit mesenteric artery induced by the selective IP agonist cicaprost. Schild plots had slopes close to unity, generating pA2 values of 8.20, 8.39 and 8.12 respectively. Non-surmountable antagonism was sometimes found with the higher concentrations of RO1138452, attributable to the EP3 contractile action of cicaprost. RO1138452 did not block relaxation of guinea-pig trachea induced by the EP2-selective agonist butaprost. In contrast, there was a modest inhibition of butaprost-induced relaxation of human pulmonary artery by RO1138452, implying activation of both EP2 and IP receptors by butaprost. RO1138452 did not affect relaxation induced by PGE2 (EP4 agonist) and substance P (NK1/endothelium-dependent agonist) in rabbit mesenteric artery. In human and rat platelet-rich plasmas, RO1138452 antagonized cicaprost-induced inhibition of platelet aggregation in a surmountable manner; pA2 values may have been affected by binding of RO1138452 to plasma protein. RO1138452 did not affect the inhibitory actions of PGD2 (DP1 agonist) and NECA (adenosine A2A agonist) in human platelets. Conclusions and implications: The data indicate that RO1138452 is a potent and selective IP receptor antagonist. RO1138452 represents an important addition to our armoury of prostanoid receptor antagonists and a potential clinical agent in situations where prostacyclin has a pathophysiological function. PMID:16880763

Jones, R L; Wise, H; Clark, R; Whiting, R L; Bley, K R

2006-01-01

301

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

PubMed

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(-7)M and the 50% relative effective concentrations (REC50) varying from 3.09×10(-7) to 5.88×10(-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. PMID:23583298

Zhang, Zhaobin; Sun, Libei; Hu, Ying; Jiao, Jian; Hu, Jianying

2013-07-01

302

The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis.  

PubMed

Peritoneal fibrosis is a complication of patients with long-term continuous ambulatory peritoneal dialysis (CAPD). Reports have indicated that angiotensin (Ang) II may correlate with the development of peritoneal fibrosis. However, it is unknown whether aldosterone also has a role in the development of peritoneal inflammation and fibrosis. The aim of the present study was to clarify the role of aldosterone in peritoneal inflammation and fibrosis. A rat model of peritoneal inflammation and fibrosis was established by daily intraperitoneal injection of dialysates and lipopolysaccharide in a 4-day interval over a period of 7 days. The animals were randomly assigned to five groups as follows: control (C); peritoneal dialysis (PD); peritoneal dialysis-spironolactone (PD-S); peritoneal dialysis-cilazapril (PD-C); and peritoneal dialysis-spironolactone-cilazapril (PD-SC). After 30 days, the TGF-?1 concentration in dialysates from all treatment groups was determined by ELISA. The histopathology of the parietal peritoneum was examined, and the expression of MCP-1, c-Jun, fibronectin (FN) and TGF-?1 in the abdominal membrane was determined by immunohistochemistry. Mineralocorticoid receptor (MR), 11?-hydroxysteroid dehydrogenase type 2 (11?-HSD2) and CYP11B2 (aldosterone synthase) were analyzed by real time-PCR. Collagen deposition was significantly higher in PD compared with the other groups. The expression of MR, 11?-HSD2 and CYP11B2 was significantly higher in PD compared with the other groups. Spironolactone and/or cilazapril treatment partially ablated the increase in monocyte chemoattractant protein (MCP)-1, p-c-Jun, transforming growth factor (TGF)-?1, FN, MR, 11?-HSD2 and CYP11B2. Furthermore, treatment with spironolactone and/or cilazapril also reduced the infiltration of CD-4- and ED-1-positive cells in rat peritoneal tissues after peritoneal fibrosis. Exogenous aldosterone may have a key role in the development of peritoneal inflammation and fibrosis. Spironolactone decreased peritoneal inflammation and fibrosis, which was associated with reduced secretion from peritoneal macrophages, inactivation of the c-Jun N-terminal kinase (JNK) pathway and subsequent downregulation of the expression of TGF-?1. PMID:24862968

Zhang, Lei; Hao, Jian-Bing; Ren, Lian-Sheng; Ding, Jiu-Li; Hao, Li-Rong

2014-08-01

303

Biochemical and pharmacological characterisatioN OF SR141716A, the first potent and selective brain cannabinoid receptor antagonist  

Microsoft Academic Search

SR141716A is a selective, potent and orally active antagonist of the brain cannabinoid receptor with a long duration of action. This compound shows high affinity for the central cannabinoid receptor (Ki=2 nM), displays low affinity for the peripheral cannabinoid receptor (Ki >1000 nM). In vitro, SR141716A antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions

Murielle Rinaldi-Carmona; Francis Barth; Michel Héaulme; Richard Alonso; David Shire; Christian Congy; Philippe Soubrié; Jean-Claude Breličre; Gérard Le Fur

1995-01-01

304

Structural determinants of A(3) adenosine receptor activation: nucleoside ligands at the agonist/antagonist boundary.  

PubMed

Mutagenesis of the human A(3) adenosine receptor (AR) suggested that certain amino acid residues contributed differently to ligand binding and activation processes. Here we demonstrated that various adenosine modifications, including adenine substitution and ribose ring constraints, also contributed differentially to these processes. The ligand effects on cyclic AMP production in intact CHO cells expressing the A(3)AR and in receptor binding were compared. Notably, the simple 2-fluoro group alone or 2-chloro in combination with N(6)-substitution dramatically diminished the efficacy of adenosine derivatives, even converting agonist into antagonist. Other affinity-increasing substitutions, including N(6)-(3-iodobenzyl) 4 and the (Northern)-methanocarba 15, also reduced efficacy, except in combination with a flexible 5'-uronamide. 2-Cl-N(6)-(3-iodobenzyl) derivatives, both in the (N)-methanocarba (i.e., of the Northern conformation) and riboside series 18 and 5, respectively, were potent antagonists with little residual agonism. Ring-constrained 2',3'-epoxide derivatives in both riboside and (N)-methanocarba series 13 and 21, respectively, and a cyclized (spiral) 4',5'-uronamide derivative 14 were synthesized and found to be human A(3)AR antagonists. 14 bound potently at both human (26 nM) and rat (49 nM) A(3)ARs. A rhodopsin-based A(3)AR model, containing all domains except the C-terminal region, indicated separate structural requirements for receptor binding and activation for these adenosine analogues. Ligand docking, taking into account binding of selected derivatives at mutant A(3)ARs, featured interactions of TM3 (His95) with the adenine moiety and TMs 6 and 7 with the ribose 5'-region. The 5'-OH group of antagonist N(6)-(3-iodobenzyl)-2-chloroadenosine 5 formed a H-bond with N274 but not with S271. The 5'-substituent of nucleoside antagonists moved toward TM7 and away from TM6. The conserved Trp243 (6.48) side chain, involved in recognition of the classical (nonnucleoside) A(3)AR antagonists but not adenosine-derived ligands, displayed a characteristic movement exclusively upon docking of agonists. Thus, A(3)AR activation appeared to require flexibility at the 5'- and 3'-positions, which was diminished in (N)-methanocarba, spiro, and epoxide analogues, and was characteristic of ribose interactions at TM6 and TM7. PMID:12238926

Gao, Zhan-Guo; Kim, Soo-Kyung; Biadatti, Thibaud; Chen, Wangzhong; Lee, Kyeong; Barak, Dov; Kim, Seong Gon; Johnson, Carl R; Jacobson, Kenneth A

2002-09-26

305

Platelet activating factor receptor antagonist improves survival and attenuates eicosanoid release in severe endotoxemia.  

PubMed Central

Exogenous platelet activating factor (PAF) causes hypotension, plasma extravasation, metabolic acidosis, and death. These effects are similar to those of endotoxin as well as the eicosanoids. A specific PAF receptor antagonist, BN52021, was used to determine its effects on the hemodynamic events, the eicosanoid production, and on survival in severe rat endotoxemia. Endotoxin alone significantly produced hypotension, prostaglandins (TxB2, PGE2) release, and death. In contrast pretreatment with BN52021, a specific PAF receptor antagonist, significantly altered the hypotension, significantly attenuated the eicosanoid release, and improved the survival rate (p less than 0.01). These findings suggest that PAF receptor activation is an early event in endotoxemia. Eicosanoid release in endotoxemia could be related to PAF synthesis and PAF receptor activation. These findings support the hypothesis that there may be an intimate relationship between PAF and the eicosanoids and that in endotoxemia some of the effects of PAF may be mediated via the cyclo-oxygenase pathway. PMID:2178565

Fletcher, J R; DiSimone, A G; Earnest, M A

1990-01-01

306

Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis.  

PubMed Central

Interleukin 1 (IL-1) receptor antagonist (IL-1ra) is a naturally occurring protein that binds to the IL-1 receptor present on T cells, fibroblasts, and other cell types and acts to block IL-1-induced responses. IL-1ra is a pure antagonist and has no agonist activity in in vitro or in vivo systems. By site-specific mutagenesis, an analog of IL-1ra was created that contained a substitution of a single amino acid, Lys-145----Asp. This analog, IL-1ra K145D, exhibited partial agonist activity in the D10.G4.1 cell proliferation assay. The newly acquired agonist activity could not be neutralized by antisera to IL-1 alpha or IL-1 beta, but it could be blocked by a monoclonal antibody to the T-cell IL-1 receptor. The analog also showed agonist activity as assayed by increased prostaglandin E2 synthesis from CHO cells expressing recombinant mouse IL-1 receptor. These results with IL-1ra K145D demonstrate the importance of the region surrounding the corresponding Asp-145 residue in IL-1 beta for triggering the biological response to IL-1. Images PMID:1826365

Ju, G; Labriola-Tompkins, E; Campen, C A; Benjamin, W R; Karas, J; Plocinski, J; Biondi, D; Kaffka, K L; Kilian, P L; Eisenberg, S P

1991-01-01

307

Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-D-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain  

PubMed Central

Underlying below-level cutaneous hypersensitivity observed following spinal cord injury (SCI) is a concurrent loss of inhibition with an increase in excitation in the spinal dorsal horn. Thus, a dual pharmacological approach, increasing spinal ?-aminobutyrate (GABA) inhibition and decreasing N-methyl-D-aspartate (NMDA) receptor-mediated excitation, could be more beneficial than either approach alone. The current study evaluated the antinociceptive effects of lumbar intrathecal (i.t.) administration of GABA receptor agonists and NMDA receptor antagonists alone and in combination in rats with neuropathic SCI pain. Rats developed markedly decreased hind paw withdrawal thresholds following an acute thoracic spinal cord compression, indicative of below-level hypersensitivity. Separately, i.t. GABAA receptor agonist muscimol and GABAB receptor agonist baclofen demonstrated dose-dependent antinociception, whereas i.t. NMDA receptor antagonist ketamine and the endogenous peptide [Ser1]histogranin, a putative NMDA receptor antagonist, demonstrated no efficacy. The combination of baclofen and ketamine resulted in a supra-additive (synergistic) antinociception whereas the combinations with muscimol were merely additive. Intrathecal pretreatment with the GABAB receptor antagonist CGP 35348 prevented the antinociceptive effect of the baclofen and ketamine combination. The data indicate that blocking spinal NMDA receptors alone is not sufficient to ameliorate SCI hypersensitivity, whereas a combined approach, simultaneous activation of spinal GABAB receptors and NMDA receptors blockade with ketamine, leads to significant antinociception. By engaging diverse pain modulating systems at the spinal level, combination drug treatment may be a useful approach in treating neuropathic SCI pain. PMID:22449374

Hama, Aldric; Sagen, Jacqueline

2012-01-01

308

Galanin receptor antagonists M40 and C7 block galanin-induced feeding.  

PubMed

Two peptide antagonists of the galanin receptor, M40 (galanin[1-13]-Pro-Pro-[Ala-Leu]2-Ala amide) and C7 (galanin[1-13]-spantide amide), significantly inhibited galanin-induced consumption of a palatable wet cookie mash, when microinjected intraventricularly to satiated rats. Antagonists were effective at doses equimolar to or less than the active doses of galanin. Feeding induced by an overnight fast was not significantly different in rats microinjected with saline as compared to M40 or C7, at doses which inhibited galanin-induced feeding. The activity of the chimeric compound, C7, did not appear to be linked to the properties of its C-terminal spantide-like sequence, as C7 did not induce barrel rolling at doses which inhibited galanin-induced feeding. The IC50 for displacement of 125I-[Tyr26]-porcine galanin 1-29 binding in rat hypothalamic membranes was 15 nM for M40, and 0.2 nM for C7, as compared to 0.8 nM for unlabelled porcine galanin(1-29). These two structurally different galanin antagonists, both demonstrating antagonist activity in vivo in awake, behaving rats, provide promising tools for further analyses of the functional activity of galanin in the mammalian brain. PMID:7679604

Crawley, J N; Robinson, J K; Langel, U; Bartfai, T

1993-01-15

309

Monovalent mannose-based DC-SIGN antagonists: targeting the hydrophobic groove of the receptor.  

PubMed

Dendritic cell-specific, intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a C-type lectin expressed specifically on dendritic cells. It is a primary site for recognition and binding of various pathogens and thus a promising therapeutic target for inhibition of pathogen entry and subsequent prevention of immune defense cell infection. We report the design and synthesis of d-mannose-based DC-SIGN antagonists bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties incorporated to target the hydrophobic groove of the receptor. The designed glycomimetics were evaluated by in vitro assay of the isolated DC-SIGN extracellular domain for their ability to compete with HIV-1 gp120 for binding to the DC-SIGN carbohydrate recognition domain. Compounds 14d and 14e, that display IC50 values of 40 ?M and 50 ?M, are among the most potent monovalent DC-SIGN antagonists reported. The antagonistic effect of all the synthesized compounds was further evaluated by a one-point in vitro assay that measures DC adhesion. Compounds 14d, 14e, 18d and 18e were shown to act as functional antagonists of DC-SIGN-mediated DC adhesion. The binding mode of 14d was also studied by molecular docking and molecular dynamics simulation, which revealed flexibility of 14d in the binding site and provides a basis for further optimization. PMID:24556146

Tomaši?, Tihomir; Hajšek, David; Švajger, Urban; Luzar, Jernej; Obermajer, Nataša; Petit-Haertlein, Isabelle; Fieschi, Franck; Anderluh, Marko

2014-03-21

310

Identification of novel androgen receptor antagonists using structure- and ligand-based methods.  

PubMed

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). The AR hormone-binding site (HBS) is intensively studied and represents the target area for current antiandrogens including Bicalutamide and structurally related Enzalutamide. As resistance to antiandrogens invariably emerges in advanced prostate cancer, there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes. Given the wealth of structural information on the AR in complex with a variety of ligands, we have applied an integrated structure- and ligand-based virtual screening methodology to identify novel AR antagonists. Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR. In particular, one identified compound demonstrated anti-AR potency in vitro that is comparable to the clinically used Bicalutamide. These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists. PMID:23278403

Li, Huifang; Ren, Xin; Leblanc, Eric; Frewin, Kate; Rennie, Paul S; Cherkasov, Artem

2013-01-28

311

Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson’s disease  

PubMed Central

Several selective antagonists for adenosine A2A receptors (A2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson’s disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D2 and adenosine A2A receptors in the basal ganglia. At present it is believed that A2AR antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson’s patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A2AR antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized anti-parkinsonian drug therapy, namely the existence of receptor (hetero)dimers/oligomers of G protein-coupled receptors, a topic currently the focus of intense debate within the scientific community. Dopamine D2 receptors (D2Rs) expressed in the striatum are known to form heteromers with A2A adenosine receptors. Thus, the development of heteromer-specific A2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs. PMID:21810444

Armentero, Marie Therese; Pinna, Annalisa; Ferré, Sergi; Lanciego, José Luis; Müller, Christa E.; Franco, Rafael

2011-01-01

312

Losartan, an Angiotensin II Type 1 Receptor Antagonist, Lowers Hematocrit in Posttransplant Erythrocytosis  

Microsoft Academic Search

The mechanism by which angiotensin-converting enzyme inhibitors reduce red cell mass in renal transplant recipients with erythrocytosis is unclear. To examine the role of angiotensin II in this disorder, losartan (a competitive an- tagonist of the angiotensin II type 1 (AT,) receptor) was administered to 23 patients with erythrocytosis. Fourteen pa- tients took 25 mg\\/d for 8 wk; nine others

BRUCE A. JULIAN; ROMAN R. BRANTLEY JR.; CATHERINE V. BARKER; TOMAS STOPKA; ROBERT S. GASTON; JOHN J. CURTIS; JEANNETFE Y. LEE; JOSEF T. PRCHAL

313

Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases.  

PubMed

Acetylcholine (neuronal and non-neuronal origin) regulates bronchoconstriction, and mucus secretion. It has an inflammatory effect by inducing attraction, survival and cytokine release from inflammatory cells. Muscarinic receptors throughout the bronchial tree are mainly restricted to muscarinic M1, M2 and M3 receptors. Three long-acting muscarinic receptor antagonists (LAMAs) were approved for the treatment of chronic obstructive pulmonary disease (COPD) in Europe: once-daily tiotropium bromide; once-daily glycopyrronium bromide; and twice-daily aclidinium bromide. All have higher selectivity for M3 receptors than for M2 receptors, and dissociate more slowly from the M3 receptors than they do from the M2 receptors. Some LAMAs showed anti-inflammatory effects [inhibition of neutrophil chemotactic activity and migration of alveolar neutrophils, decrease of several cytokines in the bronchoalveolar lavage (BAL) including interleukin (IL)-6, tumor necrosis factor (TNF)-? and leukotriene (LT)B4] and antiremodeling effects (inhibition of mucus gland hypertrophy and decrease in MUC5AC-positive goblet cell number, decrease in MUC5AC overexpression). In the clinic, LAMAs showed a significant improvement of forced expiratory volume in 1 second (FEV1), quality of life, dyspnea and reduced the number of exacerbations in COPD and more recently in asthma. This review will focus on the three LAMAs approved in Europe in the treatment of chronic airway diseases. PMID:24587893

Alagha, Khuder; Palot, Alain; Sofalvi, Tunde; Pahus, Laurie; Gouitaa, Marion; Tummino, Celine; Martinez, Stephanie; Charpin, Denis; Bourdin, Arnaud; Chanez, Pascal

2014-03-01

314

Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases  

PubMed Central

Acetylcholine (neuronal and non-neuronal origin) regulates bronchoconstriction, and mucus secretion. It has an inflammatory effect by inducing attraction, survival and cytokine release from inflammatory cells. Muscarinic receptors throughout the bronchial tree are mainly restricted to muscarinic M1, M2 and M3 receptors. Three long-acting muscarinic receptor antagonists (LAMAs) were approved for the treatment of chronic obstructive pulmonary disease (COPD) in Europe: once-daily tiotropium bromide; once-daily glycopyrronium bromide; and twice-daily aclidinium bromide. All have higher selectivity for M3 receptors than for M2 receptors, and dissociate more slowly from the M3 receptors than they do from the M2 receptors. Some LAMAs showed anti-inflammatory effects [inhibition of neutrophil chemotactic activity and migration of alveolar neutrophils, decrease of several cytokines in the bronchoalveolar lavage (BAL) including interleukin (IL)-6, tumor necrosis factor (TNF)-? and leukotriene (LT)B4] and antiremodeling effects (inhibition of mucus gland hypertrophy and decrease in MUC5AC-positive goblet cell number, decrease in MUC5AC overexpression). In the clinic, LAMAs showed a significant improvement of forced expiratory volume in 1 second (FEV1), quality of life, dyspnea and reduced the number of exacerbations in COPD and more recently in asthma. This review will focus on the three LAMAs approved in Europe in the treatment of chronic airway diseases. PMID:24587893

Palot, Alain; Sofalvi, Tunde; Pahus, Laurie; Gouitaa, Marion; Tummino, Celine; Martinez, Stephanie; Charpin, Denis; Bourdin, Arnaud; Chanez, Pascal

2014-01-01

315

Characterization of the serotonin1A receptor antagonist activity of WAY-100135 and spiperone.  

PubMed

The effects of the putative serotonin (5-HT)1A receptor antagonists WAY-100135 (WAY) and spiperone on the neuronal activity recorded from medullary and dorsal raphe 5-HT neurons and the inferior cardiac sympathetic nerve were investigated in chloralose anesthetized cats. We also determined the effectiveness of WAY and spiperone to antagonize the sympathoinhibitory effects of the 5-HT1A agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH DPAT). Intravenous administration of both WAY and spiperone produced a dose-related inhibition of the firing of medullary 5-HT neurons. WAY also inhibited firing of serotonergic neurons in the dorsal raphe nucleus. WAY treatment had no significant effect on inferior cardiac sympathetic nerve discharge (SND), whereas spiperone treatment caused a small, but significant, increase in SND. WAY treatment did not significantly affect 8-OH DPAT-induced inhibition of unit firing. Spiperone, however, did display antagonist activity at the presynaptic autoreceptor site. WAY and spiperone pretreatments resulted in significant rightward shifts in the 8-OH DPAT inhibition of SND dose-response curves and reversed the depressant effects of 8-OH DPAT. These results suggest that WAY and spiperone act as 5-HT1A antagonists postsynaptically, but WAY appears to have more potent agonist efficacy at the 5-HT1A presynaptic autoreceptor site in the cat. However, because all drugs were administered intravenously, conclusions regarding direct effects of WAY and spiperone on 5-HT1A receptors must be made cautiously. PMID:8301586

Escandon, N A; Zimmermann, D C; McCall, R B

1994-01-01

316

Functional potencies of dopamine agonists and antagonists at human dopamine D? and D? receptors.  

PubMed

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia. PMID:21658377

Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

2011-09-01

317

The role of NMDA receptor antagonists in nicotine tolerance, sensitization, and physical dependence: a preclinical review.  

PubMed

Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation. PMID:18452252

Jain, Raka; Mukherjee, Kaushiki; Balhara, Yatan Pal Singh

2008-04-30

318

Reversal of sibutramine-induced anorexia with a selective 5HT 2C receptor antagonist  

Microsoft Academic Search

Rationale  The monoamine reuptake inhibitor sibutramine reduces food intake but the receptor subtypes mediating the effects of sibutramine\\u000a on feeding remain to be clearly identified.\\u000a \\u000a \\u000a \\u000a \\u000a Objectives  The involvement of the 5-HT2C receptor subtype in the satiety-enhancing effects of sibutramine was investigated by examining the effects of co-administration\\u000a of sibutramine with the selective 5-HT2C receptor antagonist SB 242084\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Microstructural analyses of licking for

Suzanne Higgs; Alison J. Cooper; Nicholas M. Barnes

2011-01-01

319

PAF receptor antagonist Ginkgolide B inhibits tumourigenesis and angiogenesis in colitis-associated cancer  

PubMed Central

Platelet activating factor (PAF), a potent pro-inflammatory phospholipid, has been found to trigger tumor growth and angiogenesis through its G-protein coupled receptor (PAFR). This study was aimed to investigate the potential role of PAF in azoxymethane (AOM)/dextran sulfate sodium (DSS) induced colitis-associated cancer (CAC), using PAFR antagonist Ginkgolide B (GKB). We found GKB up-regulated serum level of PAF-AH activity. As assessed by disease activity index (DAI), histological injury scores, leukocytes infiltration, and expression of pro-inflammatory cytokines, GKB ameliorated colonic inflammation and decreased tumor number and load in mice. GKB also decreased expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor. These results suggest that PAFR antagonist might be a potential therapeutic strategy for CAC. PMID:25755731

Sun, Lei; He, Zhen; Ke, Jia; Li, Senmao; Wu, Xianrui; Lian, Lei; He, Xiaowen; He, Xiaosheng; Hu, Jiancong; Zou, Yifeng; Wu, Xiaojian; Lan, Ping

2015-01-01

320

Modified 2'-ribose small RNAs function as Toll-like receptor-7/8 antagonists.  

PubMed

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

Sioud, Mouldy

2015-01-01

321

PAF receptor antagonist Ginkgolide B inhibits tumourigenesis and angiogenesis in colitis-associated cancer.  

PubMed

Platelet activating factor (PAF), a potent pro-inflammatory phospholipid, has been found to trigger tumor growth and angiogenesis through its G-protein coupled receptor (PAFR). This study was aimed to investigate the potential role of PAF in azoxymethane (AOM)/dextran sulfate sodium (DSS) induced colitis-associated cancer (CAC), using PAFR antagonist Ginkgolide B (GKB). We found GKB up-regulated serum level of PAF-AH activity. As assessed by disease activity index (DAI), histological injury scores, leukocytes infiltration, and expression of pro-inflammatory cytokines, GKB ameliorated colonic inflammation and decreased tumor number and load in mice. GKB also decreased expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor. These results suggest that PAFR antagonist might be a potential therapeutic strategy for CAC. PMID:25755731

Sun, Lei; He, Zhen; Ke, Jia; Li, Senmao; Wu, Xianrui; Lian, Lei; He, Xiaowen; He, Xiaosheng; Hu, Jiancong; Zou, Yifeng; Wu, Xiaojian; Lan, Ping

2015-01-01

322

Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists.  

PubMed

Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min. PMID:24028535

Vilums, Maris; Zweemer, Annelien J M; Yu, Zhiyi; de Vries, Henk; Hillger, Julia M; Wapenaar, Hannah; Bollen, Ilse A E; Barmare, Farhana; Gross, Raymond; Clemens, Jeremy; Krenitsky, Paul; Brussee, Johannes; Stamos, Dean; Saunders, John; Heitman, Laura H; Ijzerman, Adriaan P

2013-10-10

323

Identification of a proliferator-activated receptor-? antagonist for the treatment of type 2 diabetes mellitus  

PubMed Central

In the present study, a novel antagonist of the peroxisome proliferator-activated receptor-? (PPAR?) was screened and identified, and a cell-based evaluation of the biological activity of this PPAR? antagonist was conducted. The aim of the study was to produce results that may provide a foundation for the development of a novel compound in the treatment of type 2 diabetes mellitus. Since obesity is the main cause of insulin resistance and type 2 diabetes, identifying a new reagent that is able to inhibit adipocyte differentiation and lipid accumulation is a feasible method of developing novel anti-diabetes drugs. The PPAR? antagonist was screened using a mammalian one-hybrid system and transcriptional activation. The effects of the compound on adipocyte differentiation were investigated by staining the preadipocytes with Oil Red O. In addition, the effects of the compound on the expression levels of genes associated with lipid metabolism were detected using quantitative polymerase chain reaction on differentiated mature 3T3-L1 adipocytes. As a PPAR? antagonist, N-((1H-benzo[d]imidazol-2-yl)methyl) aniline (Compound Q) was shown to depress the transcriptional activity and coactivator recruitment of PPAR?, as well as preadipocyte differentiation, in a concentration-dependent manner. The compound was also shown to decrease the expression levels of genes associated with PPAR?-regulated lipid metabolism. In conclusion, the compound screening platform was demonstrated to be valid, and the present study identified a novel PPAR? antagonist that was shown to effectively reduce the rate of adipocyte differentiation and the expression of genes associated with lipid metabolism. PMID:25574213

WANG, REN; DAI, LIHUA; CHEN, JINJIN

2015-01-01

324

The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor.  

PubMed

Antagonizing the action of the human nuclear xenobiotic receptor pregnane X receptor (PXR) may have important clinical implications in preventing drug-drug interactions and improving therapeutic efficacy. We provide evidence that a naturally occurring phytoestrogen, coumestrol, is an antagonist of the nuclear receptor PXR (NR1I2). In transient transfection assays, coumestrol was able to suppress the agonist effects of SR12813 on human PXR activity. PXR activity was assessed and correlated with effects on the metabolism of the anesthetic tribromoethanol and on gene expression in primary human hepatocytes. We found that coumestrol was able to suppress the effects of PXR agonists on the expression of the known PXR target genes, CYP3A4 and CYP2B6, in primary human hepatocytes as well as inhibit metabolism of tribromoethanol in humanized PXR mice. Coumestrol at concentrations above 1.0 microm competed in scintillation proximity assays with a labeled PXR agonist for binding to the ligand-binding cavity. However, mammalian two-hybrid assays and transient transcription data using ligand-binding-cavity mutant forms of PXR show that coumestrol also antagonizes coregulator recruitment. This effect is likely by binding to a surface outside the ligand-binding pocket. Taken together, these data imply that there are antagonist binding site(s) for coumestrol on the surface of PXR. These studies provide the basis for development of novel small molecule inhibitors of PXR with the ultimate goal of clinical applications toward preventing drug-drug interactions. PMID:18096694

Wang, Hongwei; Li, Hao; Moore, Linda B; Johnson, Michael D L; Maglich, Jodi M; Goodwin, Bryan; Ittoop, Olivia R R; Wisely, Bruce; Creech, Katrina; Parks, Derek J; Collins, Jon L; Willson, Timothy M; Kalpana, Ganjam V; Venkatesh, Madhukumar; Xie, Wen; Cho, Sool Y; Roboz, John; Redinbo, Matthew; Moore, John T; Mani, Sridhar

2008-04-01

325

KW-3902, a selective high affinity antagonist for adenosine A1 receptors.  

PubMed Central

1. We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), KW-3902 had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine (CGS21680), indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. 3. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 470 fmol mg-1 of protein) to a single class of recognition sites. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [3H]-KW-3902 and that of [3H]-CHA. 4. KW-3902 showed potent A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively. PMID:8732272

Nonaka, H.; Ichimura, M.; Takeda, M.; Kanda, T.; Shimada, J.; Suzuki, F.; Kase, H.

1996-01-01

326

Platelet-activating factor (PAF) receptor antagonists inhibit mitogen-induced human peripheral blood T-cell proliferation.  

PubMed

The addition of L-652,731 and L-653,150, two synthetic PAF-specific receptor antagonists, to 72 hour cultures of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear leukocytes (PBML) caused a dose-dependent inhibition of (3H)-thymidine incorporation into T-cells (IC50: 25 microM and 3.2 microM, respectively). This inhibition was not reversed by exogenous interleukin (IL)-1 and IL-2. PAF receptor antagonists did not affect the expression of IL-2 receptors (TAC-antigen) on T-cells. Exogenous PAF which by itself had no significant effect on PHA-stimulated PBML proliferation, only partially reversed the inhibition of proliferation caused by PAF receptor antagonists. These results may suggest the involvement of endogenously produced PAF in the regulation of immune reactions. PMID:2825672

Patrignani, P; Valitutti, S; Aiello, F; Musiani, P

1987-10-29

327

Virtual screening leads to the discovery of novel non-nucleotide P2Y1 receptor antagonists  

PubMed Central

The P2Y1 receptor (P2Y1R) is a G protein-coupled receptor naturally activated by extracellular ADP. Its stimulation is an essential requirement of ADP-induced platelet aggregation, thus making antagonists highly sought compounds for the development of antithrombotic agents. Here, through a virtual screening campaign based on a pharmacophoric representation of the common characteristics of known P2Y1R ligands and the putative shape and size of the receptor binding pocket, we have identified novel antagonist hits of µM affinity derived from a N,N’-bis-arylurea chemotype. Unlike the vast majority of known P2Y1R antagonists, these drug-like compounds do not have a nucleotidic scaffold or highly negatively charged phosphate groups. Hence, our compounds may provide a direction for the development of receptor probes with altered physicochemical properties. PMID:22831801

Costanzi, Stefano; Kumar, T. Santhosh; Balasubramanian, Ramachandran; Harden, T. Kendall; Jacobson, Kenneth A.

2012-01-01

328

5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease  

PubMed Central

Clinical observations have suggested that ritanserin, a 5-HT2A/C receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT2A receptor antagonist M100907 and the selective 5-HT2C receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT2A/C antagonist ritanserin and the selective 5-HT2A antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT2A receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. PMID:20361986

Ferguson, Marcus C.; Nayyar, Tultul; Deutch, Ariel Y.; Ansah, Twum A.

2010-01-01

329

First clinical description of an infant with interleukin-36-receptor antagonist deficiency successfully treated with anakinra.  

PubMed

YM is the first son of Tunisian consanguineous parents who developed, at 2 weeks of life, an erythematous and scaly eruption, with subsequent rapid evolution toward generalized pustular psoriasis. Afterward, cutaneous flares of diffuse erythematous rash and pustules involving the whole body appeared, with a once weekly periodicity. Intense irritability was present during flares without fever. Moreover, since 1 month of age the infant presented with diarrhea, dysphagia, and reduced feeding rate, with failure to thrive. Laboratory tests during acute flares showed marked leukocytosis, thrombocytosis, and anemia without C-reactive protein elevation. Skin biopsy and clinical presentation were consistent with pustular psoriasis; nevertheless, the patient did not respond to high-potency topical corticosteroids and retinoid acid. As the patient presented with repeated skin flares early after birth, as well as serious constitutional distress with failure to thrive, an autoinflammatory syndrome like interleukine-1-receptor antagonist deficiency or interleukin-36-receptor antagonist deficiency (DITRA) was considered. The hypothesis was reinforced by parental consanguinity, and absence of skin lesion improvement under standard topical treatment. Genetic analyses showed a homozygous mutation in the IL36RN gene (L27P), which represents the same mutation recently described in DITRA patients. At age 6 months we started treatment with the recombinant interleukin-1 receptor antagonist anakinra with efficacy both on constitutional symptoms and skin involvement. DITRA is a recently described autoinflammatory disease characterized by repeated flares of generalized pustular psoriasis, high fever, asthenia, and systemic inflammation. We report herein the first exhaustive clinical description of an infant with DITRA who was successfully treated with anakinra. PMID:24019411

Rossi-Semerano, Linda; Piram, Maryam; Chiaverini, Christine; De Ricaud, Dominique; Smahi, Asma; Koné-Paut, Isabelle

2013-10-01

330

Long-acting muscarinic receptor antagonists for the treatment of respiratory disease.  

PubMed

The use of muscarinic receptor antagonists in the treatment of chronic obstructive pulmonary disease (COPD) is well established. More recently, the potential for long-acting muscarinic receptor antagonists (LAMAs) in the treatment of asthma has also been investigated. While LAMAs offer advantages over short-acting muscarinic receptor antagonists, in terms of a reduced dosing frequency, there remains a need for therapies that improve symptom control throughout both the day and night, provide better management of exacerbations and deliver improved health-related quality of life. Furthermore, the potential for unwanted anticholinergic side effects, particularly cardiovascular effects, remains a concern for this class of compounds. Novel LAMAs in clinical development for the treatment of respiratory disease include: aclidinium bromide, NVA237 (glycopyrronium bromide), GP-MDI, EP-101, CHF-5259, umeclidinium bromide, CHF-5407, TD-4208, AZD8683 and V-0162. These compounds offer potential advantages in terms of onset of action, symptom control and safety. In addition, a number of LAMAs are also being developed as combination treatments with long-acting ?2-agonists (LABAs) or inhaled glucocorticosteroids, potentially important treatment options for patients who require combination therapy to achieve an optimal therapeutic response as their disease progresses. More recently, compounds such as GSK961081 and THRX-198321 have been identified that combine LAMA and LABA activity in the same molecule, and have the potential to offer the benefits of combination therapy in a single compound. Here, we review novel LAMAs and dual action compounds in clinical development, with a particular focus on how they may address the current unmet clinical needs in the treatment of respiratory disease, particularly COPD. PMID:23274274

Cazzola, Mario; Page, Clive; Matera, Maria Gabriella

2013-06-01

331

The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors  

PubMed Central

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

Mang, Géraldine M.; Dürst, Thomas; Bürki, Hugo; Imobersteg, Stefan; Abramowski, Dorothee; Schuepbach, Edi; Hoyer, Daniel; Fendt, Markus; Gee, Christine E.

2012-01-01

332

P2X7 Receptor Antagonists Display Agonist-like Effects on Cell Signaling Proteins  

PubMed Central

Background The activation of various P2 receptors (P2R) by extracellular nucleotides promotes diverse cellular events, including the stimulation of cell signaling protein and increases in [Ca2+]i. We report that some agents that can block P2X7R receptors also promote diverse P2X7R-independent effects on cell signaling. Methods We exposed native rat parotid acinar cells, salivary gland cell lines (Par-C10, HSY, HSG), and PC12 cells to suramin, DIDS (4,4?-diisothiocyano stilbene-2,2?-disulfonic acid), Cibacron Blue 3GA, Brilliant Blue G, and the P2X7R-selective antagonist A438079, and examined the activation/phosphorylation of ERK1/2, PKC?, Src, CDCP1, and other signaling proteins. Results With the exception of suramin, these agents blocked the phosphorylation of ERK1/2 by BzATP in rat parotid acinar cells; but higher concentrations of suramin blocked ATP-stimulated 45Ca2+ entry. Aside from A438079, these agents increased the phosphorylation of ERK1/2, Src, PKC?, and other proteins (including Dok-1) within minutes in an agent- and cell type-specific manner in the absence of a P2X7R ligand. The stimulatory effect of these compounds on the tyrosine phosphorylation of CDCP1 and its Src-dependent association with PKC? was blocked by knockdown of CDCP1, which also blocked Src and PKC? phosphorylation. Conclusions Several agents used as P2X7R blockers promote the activation of various signaling proteins and thereby act more like receptor agonists than antagonists. General significance Some compounds used to block P2 receptors have complicated effects that may confound their use in blocking receptor activation and other biological processes for which they are employed, including their use as blockers of various ion transport proteins. PMID:21397667

Hedden, Lee; Benes, Cyril H.; Soltoff, Stephen P.

2011-01-01

333

BF-1 - A novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs.  

PubMed

Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-?-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects. PMID:25666387

Schmitz, Beate; Ullmer, Christoph; Segelcke, Daniel; Gwarek, Mirella; Zhu, Xin-Ran; Lübbert, Hermann

2015-03-15

334

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL1 receptor antagonist  

Microsoft Academic Search

Acetaminophen (APAP) induced increases in intrahepatic expression of interleukin (IL)-1?, IL-1?, and IL-1 receptor antagonist (IL-1ra), when administered intraperitoneally. These observations prompted us to define the pathophysiological roles of IL-1ra in APAP-induced liver injury. Compared with wild-type (WT) mouse-derived hepatocytes, IL-1ra-deficient (IL-1ra KO)-derived hepatocytes exhibited more resistance against APAP but not APAP-derived major toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Moreover, the

Takuya Ishibe; Akihiko Kimura; Yuko Ishida; Tatsunori Takayasu; Takahito Hayashi; Koichi Tsuneyama; Kouji Matsushima; Ikuhiro Sakata; Naofumi Mukaida; Toshikazu Kondo

2009-01-01

335

Melanin concentrating hormone receptor 1 (MCHR1) antagonists-Still a viable approach for obesity treatment?  

PubMed

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ?2000 diverse MCHR1 and ?1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design. PMID:22954736

Högberg, Thomas; Frimurer, Thomas M; Sasmal, Pradip K

2012-10-01

336

Unusual pyrimidine participation: efficient stereoselective synthesis of potent dual orexin receptor antagonist MK-6096.  

PubMed

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

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

337

Oral efficacy of a leukotriene B4 receptor antagonist in colitic cotton-top tamarins  

Microsoft Academic Search

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

D Fretland; T Sanderson; P Smith; L Adams; R Carson; J Fuhr; J Tanner; N Clapp

1995-01-01

338

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

PubMed Central

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 affinity measurements vary considerably depending on which agonist-dependent state is being identified. The purpose of this study was to examine the antagonist affinity measurements at the Gi-coupling human H3 receptor, paying particular attention to measurements made in the presence of full agonists, partial agonists and the proxyfan protean agonist-induced state of the receptor. Results CHO cells stably expressing the human histamine H3 receptor and a CRE-SPAP reporter were used. Measurements of CRE-gene transcription and 3H-cAMP accumulation were made. A range of ligands of different agonist efficacies were determined, including some partial agonists e.g. VUF 5681. Unlike other Gi-coupled receptors, no Gs-coupled state of the receptor was detected with these ligands. Antagonist affinity measurements were constant, whether the measurements were made in the presence of a full agonist, a partial agonist or the protean agonist proxyfan. Conclusion In contrast to all three subtypes of the beta-adrenoceptors, but in keeping with the traditional pharmacological dogma, antagonist affinity measurements remained constant at the human H3 receptor, including the medium-efficacy proxyfan-induced state of the receptor and the VUF5681-induced state of the receptor. PMID:18538007

Baker, Jillian G

2008-01-01

339

Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin.  

PubMed

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

Nakamura, Hironori; Yokoyama, Haruko; Takayanagi, Risa; Yoshimoto, Koichi; Nakajima, Akihiro; Okuyama, Kiyoshi; Iwase, Osamu; Yamada, Yasuhiko

2015-03-01

340

GluN2B subunit-containing NMDA receptor antagonists prevent A?-mediated synaptic plasticity disruption in vivo  

PubMed Central

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-? protein (A?) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by A? in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented A?1–42 -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNF? mediates this deleterious action of Aß was provided by the ability of TNF? antagonists to prevent A?1–42 inhibition of plasticity and the abrogation of a similar disruptive effect of TNF? using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNF?, A?1–42 did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease. PMID:19918059

Hu, Neng-Wei; Klyubin, Igor; Anwyl, Roger; Rowan, Michael J.

2009-01-01

341

Uterine infusion of melatonin or melatonin receptor antagonist alters ovine feto-placental hemodynamics during midgestation.  

PubMed

Dietary melatonin supplementation from mid- to late gestation increases umbilical artery blood flow and causes disproportionate fetal growth. Melatonin receptors have been described throughout the cardiovascular system; however, there is a paucity of data on the function of placental melatonin receptors. The objectives of the current experiment were to determine fetal descending aorta blood flow, umbilical artery blood flow, and placental and fetal development following a 4-wk uterine infusion of melatonin (MEL), melatonin receptor 1 and 2 antagonist (luzindole; LUZ), or vehicle (CON) from Day 62 to Day 90 of gestation. After 4 wk of infusion, umbilical artery blood flow and umbilical artery blood flow relative to placentome weight were increased (P < 0.05) in MEL- versus CON- and LUZ-infused dams. Fetal descending aorta blood flow was increased (P < 0.05) in MEL- versus CON- and LUZ-infused dams, while fetal descending aorta blood flow relative to fetal weight was increased in MEL- versus CON-infused dams and decreased in LUZ- versus CON-infused dams. Following the 4-wk infusion, we observed an increase in placental efficiency (fetal-placentome weight ratio) in MEL- versus LUZ-infused dams. The increase in umbilical artery blood flow due to chronic uterine melatonin infusion is potentiated by an increased fetal cardiac output through the descending aorta. Moreover, melatonin receptor antagonism decreased fetal descending aorta blood flow relative to fetal weight. Therefore, melatonin receptor activation may partially mediate the observed increase in fetal blood flow following dietary melatonin supplementation. PMID:23782836

Lemley, Caleb O; Camacho, Leticia E; Vonnahme, Kimberly A

2013-08-01

342

In Hamsters the D1 Receptor Antagonist SCH 23390 Depresses Ventilation during Hypoxia  

PubMed Central

During exposure of animals to hypoxia, brain and blood dopamine levels increase stimulating dopaminergic receptors which influence the integrated ventilatory response to low oxygen. The purpose of the present study is to test the hypothesis, that in conscious hamsters, systemic antagonism of D1 receptors would depress their breathing in air and in response to hypoxic and hypercapnic challenges. Nine male hamsters were treated with saline or 0.25 mg/kg SCH-23390 (SCH), a D1 receptor antagonist that crosses the blood-brain barrier. Ventilation was determined using the barometric method and oxygen consumption and CO2 production were evaluated utilizing the flow-through method. During exposure to air, SCH decreased frequency of breathing. During exposure to hypoxia (10% oxygen in nitrogen), relative to saline, SCH-treated hamsters decreased minute ventilation by decreasing tidal volume and oxygen consumption but not CO2 production. During exposure to hypercapnia (5% CO2 in 95% O2) frequency of breathing was decreased with SCH, but there was no significant effect on minute ventilation. Relative to saline treatment body temperature was lower in SCH treated hamsters by 0.6 degrees Celsius. These results demonstrate that in hamsters D1 receptors can modulate control of ventilation in air and during hypoxia and hypercapnic exposures. Whether D1 receptors located centrally or on carotid bodies modulate these effects is not clear from this study. PMID:18036574

Schlenker, Evelyn H.

2008-01-01

343

Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.  

PubMed

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

Nikolic, Katarina; Filipic, Slavica; Agbaba, Danica; Stark, Holger

2014-07-01

344

Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H? receptor antagonists.  

PubMed

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

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

345

A representative retinoid X receptor antagonist UVI3003 induced teratogenesis in zebrafish embryos.  

PubMed

Retinoid X receptor (RXR) interfering activity has been detected in different water resources. To study RXR disruptor-induced toxicological effects on vertebrates, embryos of zebrafish (Danio rerio) were exposed to a representative RXR antagonist UVI3003. Results showed that the teratogenic index (LC50 /EC50 ) of UVI3003 was as high as 5.4. UVI3003 induced multiple malformations of embryos, including deformed fins, reduced brains, small jaws, bent tails and edema in hearts, the degree of which became more severe with increasing exposure concentration. Although no significant difference was observed in the hatching rates between the exposure group and control, the whole body length was significantly reduced by 6.5% and 8.9% when exposed to 200 and 300?µg?l(-1) of UVI3003, respectively. The heart rate also significantly decreased by 8.8-50.2% during exposure. Further experiments revealed that the pharyngula stage was the most sensitive development phase in terms of embryo response to UVI3003. The results demonstrated severe teratogenicity of RXR antagonist in zebrafish embryos and provided important data for ecotoxicological evaluation of RXR antagonists. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25186191

Zheng, Liang; Xu, Ting; Li, Daoji; Zhou, Junliang

2015-03-01

346

Development of Novel CH223191-Based Antagonists of the Aryl Hydrocarbon Receptor  

PubMed Central

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates genes involved in drug/xenobiotic metabolism, cell cycle progression, cell fate determination, immune function, and inflammatory response. Increasing evidence that AHR plays a role in the pathophysiology of a number of human disease states is driving the need for improved pharmacological tools to be used for understanding the in vivo impact of AHR modulation. In this study, we have characterized and used structure-activity relationship analyses of a newly synthesized library of derivatives of the potent AHR antagonist 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH223191). Initial screening of these compounds revealed that those bearing groups with strong electronegativity at the R1 position (i.e., CHD-5, CHD-11, and CHD-12) versus those that are more electron-poor at this position (i.e., CHD-7 and CHD-8) elicited the most potent AHR antagonistic properties. The ability of these derivatives to inhibit agonist (2,3,7,8-tetrachlorodibenzo-p-dioxin) binding, nuclear translocation of AHR, and agonist-induced enzyme activity also were determined and support the initial findings. Furthermore, CH223191, but not CHD-5, CHD-11, or CHD-12, was found to exhibit AHR-independent proproliferative properties. These results contribute to our understanding of the structural requirements of potent AHR antagonists and the development of effective pharmacological tools to be used for studying the pathophysiological role of AHR. PMID:21967751

Choi, Eun-Young; Lee, Hyosung; Dingle, R. W. Cameron; Kim, Kyung Bo

2012-01-01

347

Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.  

PubMed

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials. PMID:15771462

De Lucca, George V; Kim, Ui Tae; Vargo, Brian J; Duncia, John V; Santella, Joseph B; Gardner, Daniel S; Zheng, Changsheng; Liauw, Ann; Wang, Zhang; Emmett, George; Wacker, Dean A; Welch, Patricia K; Covington, Maryanne; Stowell, Nicole C; Wadman, Eric A; Das, Anuk M; Davies, Paul; Yeleswaram, Swamy; Graden, Danielle M; Solomon, Kimberly A; Newton, Robert C; Trainor, George L; Decicco, Carl P; Ko, Soo S

2005-03-24

348

Successful Treatment of Castleman’s Disease with Interleukin-1 Receptor Antagonist (Anakinra)  

PubMed Central

Castleman’s disease (CD) is a very rare lymphoproliferative disorder whose underlying pathophysiology is not fully understood and for which no standard treatment exists. Because interleukin-1 (IL-1) might promote the production of interleukin-6 (IL-6), a key pathogenic factor for the disease, we hypothesized that blocking the IL-1 receptor would be a useful therapy for CD. We report the case of a 61-year-old woman with CD who had undergone multiple treatments, including cladribine, rituximab, steroids, etanercept, and anti-IL-6 monoclonal antibody, and whose disease was refractory to all of these treatments. She was started on the recombinant IL-1 receptor antagonist, Anakinra, at a subcutaneous dose of 100 mg daily. Within one week, her fatigue and anorexia markedly improved, and her laboratory abnormalities, including anemia, thrombocytosis, leukocytosis, and elevated markers of inflammation, all resolved. Our observation suggests that Anakinra may be an attractive therapeutic approach for refractory multicentric CD. PMID:20501803

El-Osta, Hazem; Janku, Filip; Kurzrock, Razelle

2011-01-01

349

Successful treatment of Castleman's disease with interleukin-1 receptor antagonist (Anakinra).  

PubMed

Castleman's disease (CD) is a very rare lymphoproliferative disorder whose underlying pathophysiology is not fully understood and for which no standard treatment exists. Because interleukin-1 (IL-1) might promote the production of interleukin-6 (IL-6), a key pathogenic factor for the disease, we hypothesized that blocking the interleukin-1 receptor would be a useful therapy for CD. We report the case of a 61-year-old woman with CD who had undergone multiple treatments, including cladribine, rituximab, steroids, etanercept, and anti-IL-6 monoclonal antibody, and whose disease was refractory to all of these treatments. She was started on the recombinant IL-1 receptor antagonist, Anakinra, at a subcutaneous dose of 100 mg daily. Within one week, her fatigue and anorexia markedly improved, and her laboratory abnormalities, including anemia, thrombocytosis, leukocytosis, and elevated markers of inflammation, all resolved. Our observation suggests that Anakinra may be an attractive therapeutic approach for refractory multicentric CD. PMID:20501803

El-Osta, Hazem; Janku, Filip; Kurzrock, Razelle

2010-06-01

350

Recent progress in the development of agonists and antagonists for melatonin receptors.  

PubMed

The various physiological actions of the neurohormone melatonin are mediated mainly by two G-protein-coupled MT(1) and MT(2) receptors. The melatoninergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and PD-6735, are high-affinity nonselective MT(1) and MT(2) agonists. However, exploring the exact physiological role of the MT(1) and MT(2) melatonin receptors requires subtype selective MT(1) and MT(2) ligands. This review covers novel melatoninergic agonists and antagonists published since 2010, focusing on high-affinity and subtype selective agents. Additionally, compounds not mentioned in the previous review articles and ligands selective for the MT(3) binding site are included. PMID:22680635

Zlotos, D P

2012-01-01

351

The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison  

Microsoft Academic Search

Rationale: Antagonists at the metabotropic glu- tamate 5(mGlu5) receptorproduce robustanxiolytic effects in a number of rat tests. However, there is evidence that mGlu5 receptor antagonists may also impair working mem- ory and spatial learning following intracerebroventricular administration. Objectives: The aim of this study is to compare the effect of the potent and selective mGlu5 receptorantagonist,2-methyl-6-(phenylethynyl)-piperidine (MPEP), administered systemically on rodent

Theresa M. Ballard; Marie L. Woolley; Eric Prinssen; Jörg Huwyler; Richard Porter; Will Spooren

2005-01-01

352

Identification and characterisation of SB366791, a potent and selective vanilloid receptor (VR1\\/TRPV1) antagonist  

Microsoft Academic Search

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

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

353

Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.  

PubMed

We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits. PMID:25557493

Ko?aczkowski, Marcin; Marcinkowska, Monika; Bucki, Adam; ?niecikowska, Joanna; Paw?owski, Maciej; Kazek, Grzegorz; Siwek, Agata; Jastrz?bska-Wi?sek, Magdalena; Partyka, Anna; Wasik, Anna; Weso?owska, Anna; Mierzejewski, Pawe?; Bienkowski, Przemyslaw

2015-03-01

354

Androgen Receptor Silences Thioredoxin-interacting Protein and Competitively Inhibits Glucocorticoid Receptor-Mediated Apoptosis in Pancreatic ?-Cells.  

PubMed

Androgen receptor (AR) is known to bind to the same cis-element that glucocorticoid receptor (GR) binds to. However, the effects of androgen signaling on glucocorticoid signaling have not yet been elucidated. Here, we investigated the effects of testosterone on dexamethasone (DEX, a synthetic glucocorticoid)-induced apoptosis of pancreatic ?-cells, which might be involved in the pathogenesis of type 2 diabetes mellitus in males. We used INS-1 #6 cells, which were isolated from the INS-1 pancreatic ?-cell line and which express high levels of AR. Testosterone and dihydrotestosterone inhibited apoptosis induced by DEX in INS-1 #6 cells. AR knockdown and the AR antagonist hydroxyflutamide each diminished the anti-apoptotic effects of testosterone. AR was localized in the nucleus of both INS-1 #6 cells and pancreatic ?-cells of male rats. Induction of thioredoxin-interacting protein (TXNIP) is known to cause pro-apoptotic effects in ?-cells. Testosterone suppressed the DEX-induced increase of TXNIP at the transcriptional level. A Chromatin immunoprecipitation assays showed that both AR and GR competitively bound to the TXNIP promoter in ligand-dependent manners. Recombinant DNA-binding domain of AR bound to the same cis-element of the TXNIP promoter that GR binds to. Our results show that AR and GR competitively bind to the same cis-element of TXNIP promoter as a silencer and enhancer, respectively. These results indicate that androgen signaling functionally competes with glucocorticoid signaling in pancreatic ?-cell apoptosis. J. Cell. Biochem. 116: 998-1006, 2015. © 2015 Wiley Periodicals, Inc. PMID:25639671

Harada, Naoki; Katsuki, Takahiro; Takahashi, Yuji; Masuda, Tatsuya; Yoshinaga, Mariko; Adachi, Tetsuya; Izawa, Takeshi; Kuwamura, Mitsuru; Nakano, Yoshihisa; Yamaji, Ryoichi; Inui, Hiroshi

2015-06-01

355

Novel selective antagonist of the cannabinoid CB 1 receptor, MJ15, with prominent anti-obesity effect in rodent models  

Microsoft Academic Search

MJ15, a novel cannabinoid CB1 receptor selective antagonist was discovered. In receptor binding assays, MJ15 displayed a high affinity for rat cannabinoid CB1 receptor (Ki=27.2pM, and IC50=118.9pM), but a much lower affinity for rat cannabinoid CB2 receptor (only 46% inhibition at 10?M). At the cellular level, the IC50 values against activation of cannabinoid CB1 and CB2 receptors induced by Win55212-2

Wei Chen; Huoling Tang; Hongying Liu; Long Long; Zehui Gong; Jianquan Zheng; Mugen Chi; Yunde Xie; Zhibing Zheng; Song Li; Lili Wang

2010-01-01

356

Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects.  

PubMed

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

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

357

Biological and Conformational Evaluation of Bifunctional Compounds for Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists Possessing Two Penicillamines  

PubMed Central

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

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

358

Effect of ?{sub 7} nicotinic acetylcholine receptor agonists and antagonists on motor function in mice  

SciTech Connect

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels found throughout the body, and serve to mediate diverse physiological functions. Muscle-type nAChRs located in the motor endplate region of muscle fibers play an integral role in muscle contraction and thus motor function. The toxicity and teratogenicity of many plants (which results in millions of dollars in losses annually to the livestock industry) are due to various toxins that bind to nAChRs including deltaline and methyllycaconitine (MLA) from larkspur (Delphinium) species, and nicotine and anabasine from tobacco (Nicotiana) species. The primary result of the actions of these alkaloids at nAChRs is neuromuscular paralysis and respiratory failure. The objective of this study was to further characterize the motor coordination deficiencies that occur upon exposure to a non-lethal dose of nAChR antagonists MLA and deltaline as well as nAChR agonists nicotine and anabasine. We evaluated the effect of nAChR agonists and antagonists on the motor function and coordination in mice using a balance beam, grip strength meter, rotarod, open field analysis and tremor monitor. These analyses demonstrated that within seconds after treatment the mice had significant loss of motor function and coordination that lasted up to 1 min, followed by a short period of quiescence. Recovery to normal muscle coordination was rapid, typically within approximately 10 min post-dosing. However, mice treated with the nAChR agonist nicotine and anabasine required a slightly longer time to recover some aspects of normal muscle function in comparison to mice treated with the nAChR antagonist MLA or deltaline. -- Highlights: ? Mice treated with nAChR agonists and antagonists have a loss in motor function. ? These deficits are temporary as near normal motor function returns within 10 min. ? There are compound-specific differences in the effects on motor function.

Welch, Kevin D., E-mail: kevin.welch@ars.usda.gov [USDA/ARS Poisonous Plant Research Laboratory, 1150 E. 1400N., Logan, UT 84341 (United States); Pfister, James A. [USDA/ARS Poisonous Plant Research Laboratory, 1150 E. 1400N., Logan, UT 84341 (United States)] [USDA/ARS Poisonous Plant Research Laboratory, 1150 E. 1400N., Logan, UT 84341 (United States); Lima, Flavia G. [Federal University of Goías, School of Veterinary Medicine, Goiânia, Goías (Brazil)] [Federal University of Goías, School of Veterinary Medicine, Goiânia, Goías (Brazil); Green, Benedict T.; Gardner, Dale R. [USDA/ARS Poisonous Plant Research Laboratory, 1150 E. 1400N., Logan, UT 84341 (United States)] [USDA/ARS Poisonous Plant Research Laboratory, 1150 E. 1400N., Logan, UT 84341 (United States)

2013-02-01

359

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.  

PubMed

Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone-growth hormone-insulin-like growth factor-1 (GHRH-GH-IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific transcription factor-1, GHRH-R splice variant 1, GHRH, and GH following LPS insult. Elevation of GHRH-R and GH receptor was localized on the epithelium of the iris and ciliary body, and GHRH-R was confined to the infiltrating macrophages and leukocytes in aqueous humor but not to those in stroma. Treatment with GHRH-R antagonist decreased LPS-stimulated surges of GH and IGF1 in aqueous humor and alleviated inflammation by reducing the infiltration of macrophages and leukocytes and the production of TNF-?, IL-1?, and monocyte chemotactic protein-1. Our results indicate that inflammation in the iris and ciliary body involves the activation of GHRH signaling, which affects the recruitment of immune cells and the production of proinflammatory mediators that contribute to EIU pathogenesis. Moreover, the results suggest that GHRH-R antagonists are potential therapeutic agents for the treatment of acute ocular inflammation. PMID:25489106

Qin, Yong Jie; Chan, Sun On; Chong, Kelvin Kam Lung; Li, Benjamin Fuk Loi; Ng, Tsz Kin; Yip, Yolanda Wong Ying; Chen, Haoyu; Zhang, Mingzhi; Block, Norman L; Cheung, Herman S; Schally, Andrew V; Pang, Chi Pui

2014-12-23

360

Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.  

PubMed

Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen. PMID:25787734

Glicklich, Daniel; Frishman, William H

2015-04-01

361

Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function  

PubMed Central

Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+ cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5?-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophils in vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies. PMID:24971371

Theron, A. J.; Steel, H. C.; Tintinger, G. R.; Gravett, C. M.; Anderson, R.; Feldman, C.

2014-01-01

362

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

SciTech Connect

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.

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

363

The effects of glutamate receptor agonists and antagonists on mouse hypothalamic and hippocampal neuronal activity shown through manganese enhanced MRI.  

PubMed

Manganese enhanced MRI (MEMRI) is an imaging paradigm that can be used to assess neuronal activity in vivo. Here we investigate, through the use of MEMRI, the influence of receptor dynamics on neuronal activity in the hypothalamus and hippocampus focusing on the glutamate receptor signalling system. We demonstrate that intraperitoneal (i.p.) administration of monosodium glutamate (MSG) and the ionotropic glutamate receptor (iGluR) agonists NMDA and AMPA resulted in significantly increased signal intensity (SI) in the arcuate nucleus (ARC), the suprachiasmatic nucleus (SCN) and the CA3 region of the hippocampus of mice consistent with increased neuronal activity. Administration of the NMDA receptor antagonist MK-801 resulted in significantly decreased SI in the paraventricular nucleus (PVN) consistent with decreased neuronal activity. Co-administration of MSG and the AMPA receptor antagonist NBQX attenuated the increase in SI observed in the ARC from MSG alone, suggesting MEMRI may be applicable to the study of receptor dynamics in vivo. We also observed that administration of the various iGluR agonists and antagonists modulated SI in the lateral ventricle and that high dose MSG (300 mg) caused a hitherto unseen enhancement in SI in the entire cortical/subarachnoid region. In conclusion, MEMRI reveals changes in neuronal activity in response to iGluR agonists and antagonists in the CNS in vivo as well as revealing multifaceted effects beyond those attributable to neuronal activity alone. PMID:21925279

Hankir, Mohammed K; Parkinson, James R; Bloom, Stephen R; Bell, Jimmy D

2012-01-16

364

Mutation of a conserved serine in TM4 of opioid receptors confers full agonistic properties to classical antagonists.  

PubMed Central

The involvement of a conserved serine (Ser196 at the mu-, Ser177 at the delta-, and Ser187 at the kappa-opioid receptor) in receptor activation is demonstrated by site-directed mutagenesis. It was initially observed during our functional screening of a mu/delta-opioid chimeric receptor, mu delta2, that classical opioid antagonists such as naloxone, naltrexone, naltriben, and H-Tyr-Tic[psi,CH2NH]Phe-Phe-OH (TIPPpsi; Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) could inhibit forskolin-stimulated adenylyl cyclase activity in CHO cells stably expressing the chimeric receptor. Antagonists also activated the G protein-coupled inward rectifying potassium channel (GIRK1) in Xenopus oocytes coexpressing the mu delta2 opioid receptor and the GIRK1 channel. By sequence analysis and back mutation, it was determined that the observed antagonist activity was due to the mutation of a conserved serine to leucine in the fourth transmembrane domain (S196L). The importance of this serine was further demonstrated by analogous mutations created in the mu-opioid receptor (MORS196L) and delta-opioid receptor (DORS177L), in which classical opioid antagonists could inhibit forskolin-stimulated adenylyl cyclase activity in CHO cells stably expressing either MORS196L or DORS177L. Again, antagonists could activate the GIRK1 channel coexpressed with either MORS196L or DORS177L in Xenopus oocytes. These data taken together suggest a crucial role for this serine residue in opioid receptor activation. Images Fig. 3 PMID:8650158

Claude, P A; Wotta, D R; Zhang, X H; Prather, P L; McGinn, T M; Erickson, L J; Loh, H H; Law, P Y

1996-01-01

365

Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1  

NASA Astrophysics Data System (ADS)

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.

Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ĺgren, Hans; Tu, Yaoquan

2015-01-01

366

An iGlu Receptor Antagonist and Its Simultaneous Use with an Anticancer Drug for Cancer Therapy.  

PubMed

Glutamate receptor antagonists have been known to play a crucial role in the treatment of many neuronal diseases. Recently, these antagonists have also shown therapeutic effects in the treatment of cancer. In this study, an ionotropic glutamate (iGlu) receptor antagonist, 4-hydroxyphenylacetyl spermine (L1), was used concurrently with a common anticancer drug, doxorubicin (Dox), for simultaneous cancer therapy. Mesoporous silica nanoparticles (MSNPs) were employed as the delivery vehicle for both L1 and Dox by conjugating the iGlu receptor antagonist on the surface and encapsulating Dox within the mesopores. Dox was then trapped within the mesopores by functionalizing a redox-cleavable capping group on the MSNP surface, and it could be released upon exposure to the reductive glutathione. In vitro studies on B16F10 and NIH3T3 cell lines revealed that the iGlu receptor antagonist L1 exhibited therapeutic as well as targeting effects. In addition, the simultaneous use of therapeutic L1 and Dox proved to be synergistic in the treatment of cancer. The present work demonstrated the feasibility of employing a delivery system to deliver both neuroprotective drug and anticancer drug for efficient anticancer treatment. PMID:25735559

Tan, Si Yu; Ang, Chung Yen; Luo, Zhong; Li, Peizhou; Nguyen, Kim Truc; Zhao, Yanli

2015-04-13

367

Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1  

PubMed Central

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

Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ĺgren, Hans; Tu, Yaoquan

2015-01-01

368

Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9  

PubMed Central

Oligonucleotides containing an immune-stimulatory motif and an immune-regulatory motif act as antagonists of Toll-like receptor (TLR)7 and TLR9. In the present study, we designed and synthesized oligonucleotide-based antagonists of TLR7, 8 and 9 containing a 7-deaza-dG or arabino-G modification in the immune-stimulatory motif and 2?-O-methylribonucleotides as the immune-regulatory motif. We evaluated the biological properties of these novel synthetic oligoribonucleotides as antagonists of TLRs 7, 8 and 9 in murine and human cell-based assays and in vivo in mice and non-human primates. In HEK293, mouse and human cell-based assays, the antagonist compounds inhibited signaling pathways and production of a broad range of cytokines, including tumour necrosis factor alpha (TNF-?), interleukin (IL)-12, IL-6, interferon (IFN)-?, IL-1? and interferon gamma-induced protein (IP)-10, mediated by TLR7, 8 and 9. In vivo in mice, the antagonist compounds inhibited TLR7- and TLR9-mediated cytokine induction in a dose- and time-dependent fashion. Peripheral blood mononuclear cells (PBMCs) obtained from antagonist compound-treated monkeys secreted lower levels of TLR7-, 8- and 9-mediated cytokines than did PBMCs taken before antagonist administration. The antagonist compounds described herein provide novel agents for the potential treatment of autoimmune and inflammatory diseases. PMID:23396449

Kandimalla, Ekambar R.; Bhagat, Lakshmi; Wang, Daqing; Yu, Dong; Sullivan, Tim; La Monica, Nicola; Agrawal, Sudhir

2013-01-01

369

Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9.  

PubMed

Oligonucleotides containing an immune-stimulatory motif and an immune-regulatory motif act as antagonists of Toll-like receptor (TLR)7 and TLR9. In the present study, we designed and synthesized oligonucleotide-based antagonists of TLR7, 8 and 9 containing a 7-deaza-dG or arabino-G modification in the immune-stimulatory motif and 2'-O-methylribonucleotides as the immune-regulatory motif. We evaluated the biological properties of these novel synthetic oligoribonucleotides as antagonists of TLRs 7, 8 and 9 in murine and human cell-based assays and in vivo in mice and non-human primates. In HEK293, mouse and human cell-based assays, the antagonist compounds inhibited signaling pathways and production of a broad range of cytokines, including tumour necrosis factor alpha (TNF-?), interleukin (IL)-12, IL-6, interferon (IFN)-?, IL-1? and interferon gamma-induced protein (IP)-10, mediated by TLR7, 8 and 9. In vivo in mice, the antagonist compounds inhibited TLR7- and TLR9-mediated cytokine induction in a dose- and time-dependent fashion. Peripheral blood mononuclear cells (PBMCs) obtained from antagonist compound-treated monkeys secreted lower levels of TLR7-, 8- and 9-mediated cytokines than did PBMCs taken before antagonist administration. The antagonist compounds described herein provide novel agents for the potential treatment of autoimmune and inflammatory diseases. PMID:23396449

Kandimalla, Ekambar R; Bhagat, Lakshmi; Wang, Daqing; Yu, Dong; Sullivan, Tim; La Monica, Nicola; Agrawal, Sudhir

2013-04-01

370

Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor.  

PubMed

Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats. PMID:25643283

Perrey, David A; German, Nadezhda A; Decker, Ann M; Thorn, David; Li, Jun-Xu; Gilmour, Brian P; Thomas, Brian F; Harris, Danni L; Runyon, Scott P; Zhang, Yanan

2015-04-15

371

Docking-based virtual screening of potential human P2Y12 receptor antagonists.  

PubMed

Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor, and its antagonists have been widely developed as anti-coagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved satisfactory anti-thrombotic effects, leaving room for further improvement. To identify new chemical compounds as potential anti-coagulation inhibitors, we constructed a three-dimensional structure model of human P2Y12 by homology modeling based on the recently reported G-protein coupled receptor Meleagris gallopavo ?1 adrenergic receptor. Virtual screening of the modeled P2Y12 against three subsets of small molecules from the ZINC database, namely lead-like, fragment-like, and drug-like, identified a number of compounds that might have high binding affinity to P2Y12. Detailed analyses of the top three compounds from each subset with the highest scores indicated that all of these compounds beard a hydrophobic bulk supplemented with a few polar atoms which bound at the ligand binding site via largely hydrophobic interactions with the receptor. This study not only provides a structure model of P2Y12 for rational design of anti-platelet inhibitors, but also identifies some potential chemicals for further development. PMID:21474491

Chen, Hua; Dong, Xianchi; Zhou, Minyun; Shi, Haiming; Luo, Xinping

2011-05-01

372

Blockade and reversal of spinal morphine tolerance by P2X3 receptor antagonist.  

PubMed

In recent years, studies have substantiated the view that P2X3 receptors play a part in the generation and transmission of purinergic signals in inflammatory and chronic neuropathic pain. Data have also been presented to suggest that the process of P2X3 receptor antagonism inhibits inflammatory hyperalgesia, involving the spinal opioid system. The aim of this study was to investigate the effect of the selective P2X3 receptor antagonist A-317491 on the development of antinociceptive tolerance to chronic morphine administration in mice. Daily systemic injection of A-317491 attenuated the morphine-induced antinociceptive tolerance to von Frey and thermal stimuli. Repeated morphine injections alone led to a significant rightward shift in the morphine dose-response curve compared with that with A-317491. A single dose of A-317491 also showed a reversal effect in morphine-tolerant mice. In a withdrawal test, co-administration of A-317491 and morphine also reduced the naloxone-induced withdrawal symptoms compared with the morphine-alone group. Thus, we propose that the P2X3 receptor is involved in the process of morphine antinociceptive tolerance and may be a new therapeutic target in the prevention of tolerance to morphine-induced antinociception. PMID:25350728

Ma, Xiaqing; Xu, Tao; Xu, Hao; Jiang, Wei

2015-04-01

373

A review of pharmacology of NCS-382, a putative antagonist of gamma-hydroxybutyric acid (GHB) receptor.  

PubMed

Gamma-hydroxybutyric acid (GHB), a naturally occurring metabolite of gamma-aminobutyric acid (GABA), has been postulated to act as a specific agonist of GHB receptors and as well as a weak GABA(B) receptor agonist. To date, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), a semirigid compound structurally related to GHB, is the only compound reported to be an antagonist of the GHB receptor sites. In this article we review the in vivo and in vitro pharmacological properties of NCS-382 and its interaction with GHB and GABA(B) receptors. Binding studies have demonstrated that NCS-382 is a stereoselective ligand for GHB-binding sites, with both, the high and the low component of population, showing the same distribution of GHB receptors. Indeed, this compound did not display affinity for GABA(A), GABA(B), or any other known receptors, while conflicting data have been reported as to its selective antagonist action at GHB receptor. Only a few studies have shown that NCS-382 antagonizes GHB-induced effect, but a re-evaluation of all data reported in the literature suggests that the antagonistic effect of this compound could be due to an indirect action at GABA(B) receptors. As revealed by several behavioral studies, NCS-382 fails to antagonize GHB discriminative stimuli, GHB-induced inhibition of locomotor activity and ataxia or suppression of operant responses. Moreover, it is capable of either eliciting qualitatively similar effects to those of GHB or enhancing some actions of GHB. In addition, the NCS-382-sensitive electrophysiological effects of endogenous and exogenous GHB observed in vivo have not been completely replicated in vitro. The only electrophysiological action of GHB antagonized in vitro by NCS-382 required a previous blockade of GABA(B) receptors. We concluded that NCS-382 is a good ligand but not a selective antagonist for GHB receptor. PMID:15492774

Castelli, M Paola; Pibiri, Fabio; Carboni, Giovanni; Piras, A Paola

2004-01-01

374

The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold  

PubMed Central

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

2013-01-01

375

A 5HT 2C receptor antagonist potentiates a low dose amphetamine-induced conditioned place preference  

Microsoft Academic Search

This study was designed to determine whether a 5-HT2C receptor antagonist could induce a conditioned place preference indicative of reward and\\/or abuse potential. Here, we present the first evidence that a selective 5-HT2C receptor antagonist, 6-chloro-5-ethoxy-N-(pyridin-2-yl)indoline-1-carboxamide hydrochloride (CEPC), can potentiate a low dose (0.5mg\\/kg) amphetamine-induced positive conditioned place preference (CPP). CEPC did not produce any CPP given alone at doses

John D. McCorvy; Aubrie A. Harland; Rebecca Maglathlin; David E. Nichols

2011-01-01

376

The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657  

PubMed Central

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

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

377

Multivalent benzene polyphosphate derivatives are non-Ca2+-mobilizing Ins(1,4,5)P3 receptor antagonists  

PubMed Central

Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3 1] mobilizes intracellular Ca2+ through the Ins(1,4,5)P3 receptor [InsP3R]. Although some progress has been made in the design of synthetic InsP3R partial agonists and antagonists, there are still few examples of useful small molecule competitive antagonists. A “multivalent” approach is explored and new dimeric polyphosphorylated aromatic derivatives were designed, synthesized and biologically evaluated. The established weak InsP3R ligand benzene 1,2,4-trisphosphate [Bz(1,2,4)P3 2] is dimerized through its 5-position in two different ways, first directly as the biphenyl derivative biphenyl 2,2?,4,4?,5,5?-hexakisphosphate, [BiPh(2,2?,4,4?,5,5?)P6 8] and with its regioisomeric biphenyl 3,3?,4,4?,5,5?-hexakisphosphate [BiPh(3,3?,4,4?,5,5?)P6 11]. Secondly, a linker motif is introduced in a flexible ethylene-bridged dimer (9) with its corresponding 1,2-bisphosphate dimer (10), both loosely analogous to the very weak antagonist 1,2-bis(2-aminophenoxy)ethane-N,N,N?,N?-tetraacetic acid (BAPTA 7). In permeabilized L15 fibroblasts overexpressing type 1 InsP3R, BiPh(2,2?,4,4?,5,5?)P6 (8) inhibits Ins(1,4,5)P3-induced Ca2+ release in a apparently competitive fashion [IC50 187 nM] and the Bz(1,2,4)P3 dimer (9) is only slightly weaker [IC50 380 nM]. Compounds were also evaluated against type I Ins(1,4,5)P3 5-phosphatase. All compounds are resistant to dephosphorylation, with BiPh(2,2?,4,4?,5,5?)P6 (8), being the most effective inhibitor of any biphenyl derivative synthesized to date [IC50 480 nM] and the Bz(1,2,4)P3 ethylene dimer (9) weaker [IC50 3.55 ?M]. BiPh(3,3?,4,4?,5,5?)P6 (11) also inhibits 5-phosphatase [IC50 730 nM] and exhibits unexpected Ca2+ releasing activity [EC50 800 nM]. Thus, relocation of only a single mirrored phenyl phosphate group in (11) from that of antagonist (8) does not markedly change enzyme inhibitory activity, but elicits a dramatic switch in Ca2+-releasing activity. Such new agents demonstrate the power of the multivalent approach and may be useful to investigate the chemical biology of signaling through InsP3R and as templates for further design. PMID:24749014

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

2014-01-01

378

Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist.  

PubMed

The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype rec