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Selective Antagonist (selective + antagonist)
Kinds of Selective Antagonist Selected AbstractsChemInform Abstract: Aryloxypyrazines as Highly Selective Antagonists of Oxytocin.CHEMINFORM, Issue 40 2009Alan Brown Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Discovery of 2-Aminothiazole-4-carboxamides, a Novel Class of Muscarinic M3 Selective Antagonists, Through Solution-Phase Parallel Synthesis.CHEMINFORM, Issue 39 2005Yufu Sagara Abstract For Abstract see ChemInform Abstract in Full Text. [source] Preparation of Non-Peptide, Highly Potent and Selective Antagonists of Arginine Vasopressin V1A Receptor by Introduction of Alkoxy Groups.CHEMINFORM, Issue 6 2004Yoshiaki Shimada Abstract For Abstract see ChemInform Abstract in Full Text. [source] First cloning and functional characterization of a melatonin receptor in fish brain: a novel one?JOURNAL OF PINEAL RESEARCH, Issue 2 2002Pascaline Gaildrat Melatonin, a neuroendocrine transducer of photoperiod, influences a number of physiological functions and behaviors through specific seven transmembrane domains receptors. We report here the first full-length cloning and functional characterization of a melatonin receptor (P2.6) in a fish, the pike (Teleost). P2.6 encodes a protein that is ,80% identical to melatonin receptors previously isolated partially in non-mammals and classified as members of the Mel1b subtype; but, it shares only 61% identity with the full-length human Mel1b melatonin receptor (hMT2). Expression of P2.6 results in ligand binding characteristics similar to that described for endogenous melatonin receptors. Selective antagonists of the hMT2 (4-phenyl-2-propionamidotetraline and luzindole) were poor competitors of 2-[125I]iodomelatonin binding to the recombinant receptor. In Chinese hamster ovary cells expressing both the cystic fibrosis transmembrane conductance regulator chloride channel and P2.6 receptor, melatonin counteracted the forskolin induced activation of the channel. The results are best explained by a selective inhibition of the adenylyl cyclase. By reverse transcription-polymerase chain reaction, P2.6 mRNA appeared expressed in the optic tectum and, to lesser extent, in the retina and pituitary. In conclusion, these results, together with those of a phylogenetic analysis, suggest that P2.6 might belong to a distinct subtype group within the vertebrate melatonin receptor family. [source] Prostanoid receptor antagonists: development strategies and therapeutic applicationsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009RL Jones 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. [source] Effects of MPEP on expression of food-, MDMA- or amphetamine-conditioned place preference in ratsADDICTION BIOLOGY, Issue 3 2005Volker Herzig Recent studies have revealed the effectiveness of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a highly selective antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), in conditioned drug reward. In a previous study we showed that MPEP blocks expression of context-conditioned morphine- but not cocaine reward in the rat. The present study now examines the effectiveness of MPEP in the expression of context-conditioned food, MDMA (,ecstasy?) or amphetamine reward. Therefore, three groups of rats were conditioned either to food, MDMA or amphetamine in the conditioned place preference (CPP) paradigm. After conditioning, CPP expression and locomotion were determined simultaneously in the presence and absence of the respective reward (i.e. food or drug), or after application of 50?mg/kg MPEP (the dose that was most effective in reducing morphine CPP expression in our previous study). As a result, MPEP reduced locomotion in all groups. Furthermore, only expression of amphetamine CPP was inhibited by MPEP, while expression of food and MDMA CPP was not affected, suggesting that the MPEP-induced inhibition of amphetamine CPP expression was not causally linked to the reduction of locomotion. Overall, we conclude that MPEP reduces expression of context-conditioned amphetamine but not MDMA or food reward. [source] Activity-dependent modulation of GABAergic synapses in developing rat spinal networks in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Marcelo Rosato-Siri Abstract The role of activity-dependent plasticity in modulating inhibitory synapses was investigated in embryonic rat spinal cord slice cultures, by chronic exposure to non-NMDA receptor blockers. GABAergic synaptic efficacy in control and chronic-treated cultures was investigated by patch-recordings from visually identified spinal interneurons. In both culture groups proximal stimulation induced the appearance of postsynaptic currents (PSCs), which were fully antagonized by 20 µM bicuculline application and reverse polarity at potential values close to those reported for spontaneous GABAergic PSCs. In chronically treated cells GABAergic evoked PSCs displayed a larger failure rate and a smaller coefficient of variation of mean PSC amplitude, when compared to controls. As opposed to controls, chronic GABAergic evoked PSCs did not facilitate upon paired-pulse stimulation. Facilitation at chronic synapses was observed when extracellular calcium levels were decreased below physiological values (< 2 mM). Kainate was used to disclose any functional differences between control and treated slices. In accordance with the presynaptic action of kainate, the application of this drug along with GYKI, an AMPA receptor selective antagonist, changed, with analogous potency, short-term plasticity of GABAergic synapses from control and treated cultures. Nevertheless, in chronic cultures, the downstream effects of such activation unmasked short-term depression. Ultrastructural analysis of synapses in chronically treated cultures showed a reduction both in symmetric synapses and in the number of vesicles at symmetric terminals. Thus, based on electrophysiological and ultrastructural data, it could be suggested that during the development of spinal circuits, GABAergic synapses are modulated by glutamatergic transmission, and thus implying that excitatory transmission regulates the strength of GABAergic synapses. [source] The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human plateletsFEBS JOURNAL, Issue 8 2000Carol Dangelmaier U46619, a thromboxane A2 mimetic, but not ADP, caused activation of p38 mitogen activated protein (MAP) kinase in aspirin-treated platelets. In nonaspirinated human platelets ADP activated p38 MAP kinase in both a time-and concentration-dependent manner, suggesting that ADP-induced p38 MAP kinase activation requires generation of thromboxane A2. However, neither a thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 and a thromboxane synthase inhibitor, furegrelate, either alone or together, nor indomethacin blocked ADP-induced p38 kinase activation in nonaspirinated platelets. Other cycloxygenase products, PGE2, PGD2, and PGF2,, failed to activate p38 kinase in aspirin-treated platelets. Hence, ADP must be generating an agonist, other than thromboxane A2, via an aspirin-sensitive pathway, which is capable of activating p38 kinase. AR-C66096, a P2TAC (platelet ADP receptor coupled to inhibition of adenylate cyclase) antagonist, did not inhibit ADP-induced p38 MAP kinase activation. The P2X receptor selective agonist, ,,,-methylene ATP, failed to activate p38 MAP kinase. On the other hand, the P2Y1 receptor selective antagonist, adenosine-2,-phosphate-5,-phosphate inhibited ADP-induced p38 kinase activation in a concentration-dependent manner, indicating that the P2Y1 receptor alone mediates ADP-induced generation of the p38 kinase-activating factor. These results demonstrate that ADP causes the generation of a factor in human platelets, which can activate p38 kinase, and that this response is mediated by the P2Y1 receptor. Neither the P2TAC receptor nor the P2X1 receptor has any significant role in this response. [source] Evidence against ,2 -adrenoceptors mediating relaxation in rat thoracic aortae: ,2 -agonists relaxation depends on interaction with ,1 -adrenoceptorsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2006Enrique F. Castillo Abstract In rat aorta, the presence of functional ,2 -adrenoceptors (,2 -AR) was investigated in ring preparations preconstricted with ,1 -adrenergic and non- ,1 -adrenergic agonists. Particularly, the hypothetical interference of ,2 -AR agonists with ,1 -AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to ,2 -AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 × 10,6 m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (,log EC50) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, NG -nitro- l -arginine methyl ester (l -NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective ,2 -AR antagonist, rauwolscine (,1 × 10,6 m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F2, (3 × 10,7 m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration,contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the ,1D -AR selective antagonist, BMY 7378, and rauwolscine. The pA2 and pKB values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the ,1D -AR. The other selective ,2 -AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional ,2 -AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the ,1 -AR), inhibitory and excitatory, interaction with ,1 -ARs. [source] P2Y1 receptor signaling enhances neuroprotection by astrocytes against oxidative stress via IL-6 release in hippocampal culturesGLIA, Issue 3 2009Takumi Fujita Abstract Cell survival is a critical issue in the onset and progression of neurodegenerative diseases and following pathological events including ischemia and traumatic brain injury. Oxidative stress is the main cause of cell damage in such pathological conditions. Here, we report that adenosine 5,-triphosphate (ATP) protects hippocampal astrocytes from hydrogen peroxide (H2O2)-evoked oxidative injury in astrocyte monocultures. The effect of ATP was prevented by a selective antagonist of or siRNAs against P2Y1R. Interestingly, in astrocyte-neuron cocultures, ATP also produced neuroprotective effects against H2O2 -evoked neuronal cell death, whereas ATP did not produce any neuroprotective effects in monocultures. The ATP-induced neuroprotection in cocultures was completely inhibited by silencing of astrocytic P2Y1R expression, indicating that ATP acts on astrocytes and enhances their neuroprotective functions by activating P2Y1R. Furthermore, this neuroprotective effect was mimicked by applying conditioned medium from astrocytes that had been stimulated by ATP, implying an involvement of diffusible factors from astrocytes. We found that, in both purified astrocyte cultures and astrocyte-neuronal cocultures, ATP and the P2Y1R agonist 2-methylthioadenosine 5, diphosphate (2MeSADP) induced the release of interleukin-6 (IL-6), but this did not occur in neuron monocultures. Moreover, exogenous IL-6 produced a neuroprotective effect, and the neuroprotection induced by P2Y1R-stimulated astrocytes was prevented in the presence of an anti-IL-6 antibody. Taken together, these results suggest that P2Y1R-stimulated astrocytes protect against neuronal damage induced by oxidative stress, and that IL-6 is a crucial signaling molecule released from astrocytes. Thus, activation of P2Y1R in astrocytes may rescue neurons from secondary cell death under pathological conditions. © 2008 Wiley-Liss, Inc. [source] Synthesis of 1-(2,4-dichlorophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)- N -(piperidin-1-yl)-1H -pyrazole-3-carboxamide ([11C]JHU75528) and 1-(2-bromophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)- N -(piperidin-1-yl)-1H -pyrazole-3-carboxamide ([11C]JHU75575) as potential radioligands for PET imaging of cerebral cannabinoid receptorJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2006Hong Fan Abstract Two novel ligands for cerebral cannabinoid receptor (CB1), 1-(2,4-dichlorophenyl)-4-cyano-5-(4-methoxyphenyl)- N -(piperidin-1-yl)-1H -pyrazole-3-carboxamide (JHU75528) and 1-(2-bromophenyl)-4-cyano-5-(4-methoxyphenyl)- N -(piperidin-1-yl)-1H -pyrazole-3-carboxamide (JHU75575) have been synthesized. Both JHU75528 and JHU75575 display a combination of higher binding affinity and lower lipophilicity than those of Rimonabant (SR141716), a high affinity CB1 selective antagonist, and AM281, the only available ligand for emission tomography imaging of CB1 in human subjects. Radiolabeled [11C]JHU75528 and [11C]JHU75575 were prepared by reaction of [11C]methyl iodide with nor-methyl precursors. The average radiochemical yield, specific radioactivity, and radiochemical purity of [11C]JHU75528 were 16%, 235 GBq/µmol (6360 mCi/µmol), and 99%, respectively; those of [11C]JHU75575 were 8%, 196 GBq/µmol (5308 mCi/µmol), and 99%, respectively. Both ligands hold promise as PET radioligands for imaging CB1 receptor. Copyright © 2006 John Wiley & Sons, Ltd. [source] Synthesis of (R)- and (S)-[O-methyl - 11C]N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N,-(4-methoxy-phenyl)-urea as candidate high affinity ,1 -adrenoceptor PET radioligandsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2005Stefan Wagner Abstract Molecular imaging and quantification of myocardial ,1 -adrenoceptor (AR) rather than total , -AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial ,1 -AR density is reduced in patients with chronic heart failure whereas cardiac ,2 -AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess , -AR density non-invasively in humans. However, no PET radioligand for the selective imaging of cardiac ,1 -ARs is clinically available. Here some derivatives of the well characterized ,1 -AR selective antagonist, ICI 89,406, namely the enantiomers of N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N,-(4-hydroxy-phenyl)-urea (5a and 5b) were synthesized and evaluated in vitro. The (R)-isomer 5a was more ,1 -selective but has lower affinity than its (S)-enantiomer 5b (,1 -AR selectivity: 6100 vs 1240; ,1 -affinity: K1 = 0.288 nM vs K1 = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f, respectively, with [11C]iodomethane gave 11C-labelled versions of 5a and 5b, namely 5g and 5h, in 44 ± 5% radiochemical yield (decay-corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial ,1 -ARs. Copyright © 2005 John Wiley & Sons, Ltd. [source] Involvement of 5-HT3 receptors in the development and expression of methamphetamine-induced behavioral sensitization: 5-HT3A receptor channel and binding studyJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Ji-Hoon Yoo Abstract Methamphetamine (MAP) is one of the most commonly abused drugs in Asia, and previous studies suggest that serotonin 3 receptors (5-HT3) are involved in MAP-induced locomotion and reward. However, little is known about the role of 5-HT3 receptors in MAP-induced behavioral sensitization. Here, we measured the effects of MDL 72222, a 5-HT3 antagonist, and SR 57227 A, a 5-HT3 agonist, on the development and expression of MAP-induced behavioral sensitization, and alternations of 5-HT3 receptor binding labeled with the 5-HT3 -selective antagonist, [3H]GR65630, in mice. In addition, we investigated the effects of MAP on 5-HT3A receptor channel activity in Xenopus laevis oocytes expressing 5-HT3A receptors. We found that MDL 72222 attenuated both the development and expression of behavioral sensitization to MAP (1.0 mg/kg, i.p.), and that this attenuating effect of MDL 72222 was reversed by pre-treatment with SR 57227 A. In oocytes expressing 5-HT3A receptor, MAP exhibited a dual modulation of 5-HT3A receptor channel activity, i.e. pre-treatment with a low dose of MAP (0.1 µm) enhanced 5-HT-induced inward peak current (I5-HT) but a high dose of MAP (100 µm) inhibited I5-HT. The acute administration of MDL 72222 with MAP decreased [3H]GR65630 binding versus MAP alone in the mouse striatum. Our results suggest that MDL 72222 attenuates MAP-induced behavioral sensitization via 5-HT3 receptors in the caudate putamen, and that 5-HT3 receptor antagonists like MDL 72222 have potential as novel anti-psychotic agents for the treatment of MAP dependence and psychosis. [source] Long-term Infusion of Brain-Derived Neurotrophic Factor Reduces Food Intake and Body Weight via a Corticotrophin-Releasing Hormone Pathway in the Paraventricular Nucleus of the HypothalamusJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2010M. Toriya Brain-derived neurotrophic factor (BDNF) has been implicated in learning, depression and energy metabolism. However, the neuronal mechanisms underlying the effects of BDNF on energy metabolism remain unclear. The present study aimed to elucidate the neuronal pathways by which BDNF controls feeding behaviour and energy balance. Using an osmotic mini-pump, BDNF or control artificial cerebrospinal fluid was infused i.c.v. at the lateral ventricle or into the paraventricular nucleus of the hypothalamus (PVN) for 12 days. Intracerebroventricular BDNF up-regulated mRNA expression of corticotrophin-releasing hormone (CRH) and urocortin in the PVN. TrkB, the receptor for BDNF, was expressed in the PVN neurones, including those containing CRH. Both i.c.v. and intra-PVN-administered BDNF decreased food intake and body weight. These effects of BDNF on food intake and body weight were counteracted by the co-administration of ,-helical-CRH, an antagonist for the CRH and urocortin receptors CRH-R1/R2, and partly attenuated by a selective antagonist for CRH-R2 but not CRH-R1. Intracerebroventricular BDNF also decreased the subcutaneous and visceral fat mass, adipocyte size and serum triglyceride levels, which were all attenuated by ,-helical-CRH. Furthermore, BDNF decreased the respiratory quotient and raised rectal temperature, which were counteracted by ,-helical-CRH. These results indicate that the CRH-urocortin-CRH-R2 pathway in the PVN and connected areas mediates the long-term effects of BDNF to depress feeding and promote lipolysis. [source] NMDA receptors mediate an early up-regulation of brain-derived neurotrophic factor expression in substantia nigra in a rat model of presymptomatic Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2009Gonzalo Bustos Abstract The clinical symptoms of Parkinson's disease (PD) appear late and only when the degenerative process at the level of the nigrostriatal dopamine (DA) pathway is quite advanced. An increase in brain-derived neurotrophic factor (BDNF) expression may be one of the molecular signals associated to compensatory and plastic responses occurring in basal ganglia during presymptomatic PD. In the present study, we used in vivo microdialysis, semiquantitative reverse transcriptase,polymerase chain reaction, and immunohistochemistry to study N-methyl- D -aspartic acid (NMDA) receptor regulation of BDNF expression in substantia nigra (SN) of adult rats after partial lesioning of the nigrostriatal DA pathway with unilateral striatal injections of 6-hydroxydopamine (6-OHDA). A time-dependent partial decrease of striatal DA tissue content as well as parallel and gradual increases in extracellular glutamate and aspartate levels in SN were found 1 to 7 days after unilateral 6-OHDA intrastriatal injection. Instead, the number of tyrosine hydroxylase,immunoreactive (IR) cells in the ipsilateral SN pars compacta remained statistically unchanged after neurotoxin injection. Intrastriatal administration of 6-OHDA also produced an early and transient augmentation of pan-BDNF, exon II,BDNF, and exon III,BDNF transcripts in the ipsilateral SN. The pan-BDNF and exon II,BDNF transcript increases were completely abolished by the prior systemic administration of MK-801, a selective antagonist of NMDA receptors. MK-801 also blocked the increase in BDNF-IR cells in SN observed 7 days after unilateral 6-OHDA intrastriatal injections. Our findings suggest that a coupling between glutamate release, NMDA receptor activation, and BDNF expression may exist in the adult SN and represent an important signal in this midbrain nucleus triggered in response to partial DA loss occurring in striatal nerve endings during presymptomatic PD. © 2009 Wiley-Liss, Inc. [source] Suppression of melatonin biosynthesis in the chicken pineal gland by retinally perceived light , involvement of D1-dopamine receptorsJOURNAL OF PINEAL RESEARCH, Issue 2 2004Jolanta B. Zawilska Abstract:, In this study the role of retinal dopamine (DA) receptors in the light-induced suppression of melatonin biosynthesis in the chicken pineal gland was examined. Exposure of dark-adapted chickens to low intensity light (4 lux) at night significantly decreased the activity of serotonin N-acetyltransferase (AA-NAT; the penultimate and key regulatory enzyme in melatonin production) and melatonin content in the pineal gland. This suppressive action of light was blocked by intraocular (i.oc.) administration of SCH 23390 (a selective antagonist of D1-DA receptors), but was not affected by sulpiride (a selective antagonist of D2-DA receptors). Injection of DA (i.oc.) to dark-adapted chickens significantly decreased pineal AA-NAT activity and melatonin content in a dose- and time-dependent manner. The action of DA was mimicked by selective agonists of D1-DA receptors, SKF 38393 and SKF 81297, and non-hydrolyzable analogs of cyclic AMP (cAMP), dibutyryl-cAMP and 8-bromo-cAMP. However, i.oc. administration of quinpirole, a selective agonist of D2-DA receptors, did not modify pineal AA-NAT activity. In contrast, quinpirole potently decreased nocturnal AA-NAT activity in the retina. Systemic administration of SCH 23390 to chickens blocked the i.oc. DA-evoked decline in nighttime pineal AA-NAT activity, whereas sulpiride was ineffective. These findings indicate that light activation of retinal dopaminergic neurotransmission, with concomitant stimulation of D1-DA receptors positively coupled to the cAMP generating system, plays an important role in a cascade of events regulating pineal activity. [source] Ephedrine in the cat lung vasculatureACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2003A. M. Fields Background:, Ephedrine is one of the most commonly used non-catecholamine sympathomimetic agents. It is used in operating rooms and critical care settings worldwide. While it has many side effects, its ability to rapidly raise blood pressure makes it an ideal agent to maintain homeostasis as well as in emergency situations. While its effects are known to be mediated by an ,-mediated mechanism, the exact , subtype is unknown. In addition, no studies using ephedrine have been performed in the pulmonary vascular bed of the cat. Methods:, The effects of phentolamine, a non-selective ,-receptor blocker, and prazosin, an ,1 -selective antagonist, were investigated on pulmonary arterial responses to ephedrine, phenylepherine, norepinephrine, and U-46619. Lobar arterial perfusion pressure was continuously monitored, electronically averaged, and recorded with constant flow in the isolated left lower lobe vascular bed of the cat. Results:, Phentolamine and prazosin significantly reduced vasoconstrictor pulmonary perfusion pressure increases induced by ephedrine. Conclusion:, Ephedrine has significant vasopressor activity in the pulmonary vascular bed of the cat meditated predominantly by ,1 adrenergic receptor activation. [source] Central and peripheral role of the nociceptin/orphaninFQ system on normal and disturbed colonic motor function and faecal pellet output in the ratNEUROGASTROENTEROLOGY & MOTILITY, Issue 8 2008M. Broccardo Abstract, In this study, seeking further information on the role of the nociceptin/orphanin FQ (N/OFQ)-ergic system in normal and disturbed colonic motor function in rats, we compared the colonic effects of UFP-112, a novel highly potent agonist, with those of N/OFQ. When injected intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.), UFP-112 and N/OFQ increased bead expulsion time in a statistically significant and dose-related manner and reduced the percentage of rats with castor oil-induced diarrhoea. UFP-112 showed greater efficacy, higher potency and longer-lasting inhibitory effects than N/OFQ, and pretreatment with UFP-101, a selective antagonist, blocked the N/OFQ analogue-induced responses in both tests. When injected i.c.v., UFP-112 and N/OFQ inhibited corticotrophin releasing factor- and restrain stress-stimulated faecal pellet excretion significantly and in a dose-related manner. Conversely, when injected peripherally both peptides significantly inhibited colonic propulsive motility but did so in a non-dose-related manner. In conclusion, these findings indicate that, in the rat, the central and peripheral N/OFQ systems have an inhibitory role in modulating distal colonic propulsive motility under physiological and pathological conditions. UFP-112 therefore promises to be a useful pharmacological tool for investigating the role of the N/OFQ system in motor functions in the distal colonic tract under physiological and pathological conditions. [source] Urodynamic effects of silodosin, a new ,1A -adrenoceptor selective antagonist, for the treatment of benign prostatic hyperplasia,,NEUROUROLOGY AND URODYNAMICS, Issue 4 2010Tomonori Yamanishi Abstract Aims To investigate urodynamically the effects of silodosin, a new ,1A -adrenoceptor-selective antagonist, in the treatment of benign prostatic hyperplasia (BPH). Methods Thirty six male patients with BPH (69.9,±,7.3 years), who were referred as candidates for surgery, were treated with silodosin (4,mg twice daily). The total International Prostate Symptom Score (IPSS) was 20.7,±,7.4, maximum flow rate (Qmax) was 6.7,±,3.0,ml/sec, and prostate volume was 45.6,±,24.5,ml. Results Total IPSS, storage and voiding symptom subscores and QOL score decreased significantly, and Qmax increased significantly after 1,12 months of therapy (all P,<,0.05). In urodynamic study (n,=,29), maximum cystometric capacity increased significantly (P,=,0.0027), and detrusor overactivity disappeared in 8 of 20 patients (40%) and improved (bladder capacity increased more than 50%) in 7 (35%) after the therapy. In pressure/flow studies (n,=,27), the obstruction grade was improved in 15 patients (56%). Detrusor opening pressure, detrusor pressure at Qmax, bladder outlet obstruction index, and Schäfer's obstruction class decreased significantly after therapy (all P,<,0.01). After 12 months, 16 patients (44%) are still on silodosin for 23.3,±,7.0 (range 12,36) months, and the improvements in IPSS and Qmax were stable. Twenty patients withdrew because of insufficient effectiveness in 13 patients (12 patients underwent surgery), side effects in 3, and unknown reasons in 4. Conclusion Silodosin appears to improve detrusor overactivity and obstruction grade in patients with BPH. With silodosin treatment, LUTS could be managed effectively for more than a year in at least 44% of the patients. Neurourol. Urodynam. 29:558,562, 2010. © 2009 Wiley-Liss, Inc. [source] Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidolAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2001Kazuo Mihara Abstract The dopamine D2 receptor (DRD2) gene has a Taq1 A restriction fragment length polymorphism yielding two alleles, A1 and A2. We have previously shown that female patients with the A1 allele show greater prolactin response to nemonapride, a selective antagonist for D2-like dopamine receptors, in schizophrenic patients. In the present study, the relationship between this polymorphism and prolactin response to bromperidol was investigated in 32 untreated schizophrenic inpatients (16 males, 16 females). The daily dose of bromperidol was fixed at 6 (n,=,10), 12 (n,=,13), or 18 mg (n,=,9) during a 2-week treatment period. Taq1 A genotypes were determined by PCR method. Plasma prolactin concentration was measured by radioimmunoassay. Plasma concentration of bromperidol was measured by HPLC method. The subjects were divided into four subgroups by gender and the genotypes, i.e., 10 males and 11 females with the A1 allele, 6 males and 5 females with no A1 allele. The females with the A1 allele had the highest , prolactin (the change from the pretreatment concentration)/bromperidol concentration ratio among the other groups (P,<,0.05). The present study thus suggests that female patients with the A1 allele show greater prolactin response to bromperidol, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia. © 2001 Wiley-Liss, Inc. [source] Pre- and postsynaptic modulation of monosynaptic reflex by GABAA receptors on turtle spinal cordTHE JOURNAL OF PHYSIOLOGY, Issue 14 2010Wendy Bautista There is growing evidence that activation of high affinity extrasynaptic GABAA receptors in the brain, cerebellum and spinal cord substantia gelatinosa results in a tonic inhibition controlling postsynaptic excitability. The aim of the present study was to determine if GABAA receptors mediating tonic inhibition participate in the modulation of monosynaptic reflex (MSR) in the vertebrate spinal cord. Using an in vitro turtle lumbar spinal cord preparation, we show that conditioning stimulation of a dorsal root depressed the test monosynaptic reflex (MSR) at long condition,test intervals. This long duration inhibition is similar to the one seen in mammalian spinal cord and it is dependent on GABAA as it was completely blocked by 20 ,m picrotoxin (PTX) or bicuculline (BIC) or 1 ,m gabazine, simultaneously depressing the dorsal root potential (DRP) without MSR facilitation. Interestingly 100 ,m picrotoxin or BIC potentiated the MSR, depressed the DRP, and produced a long lasting motoneurone after-discharge. Furosemide, a selective antagonist of extrasynaptic GABAA receptors, affects receptor subtypes with ,4/6 subunits, and in a similar way to higher concentrations of PTX or BIC, also potentiated the MSR but did not affect the DRP, suggesting the presence of ,4/6 GABAA receptors at motoneurones. Our results suggest that (1) the turtle spinal cord has a GABAA mediated long duration inhibition similar to presynaptic inhibition observed in mammals, (2) GABAA receptors located at the motoneurones and primary afferents might produce tonic inhibition of monosynaptic reflex, and (3) GABAA receptors modulate motoneurone excitability reducing the probability of spurious and inappropriate activation. [source] ORIGINAL ARTICLE: Urocortin Increases IL-4 and IL-10 Secretion and Reverses LPS-induced TNF-, Release from Human Trophoblast Primary CellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 4 2009Michela Torricelli Problem, As urocortin (Ucn) is a placental peptide belonging to the corticotrophin-releasing hormone (CRH) family that modulates immune function in other biological models, this study evaluated Ucn effects on cytokines secretion from cultured human trophoblast cells. Method of study, Placentas were collected from normal term pregnancies after elective caesarean section, and primary trophoblast culture was prepared followed by the treatment of Ucn and/or CRH selective antagonists, antalarmin and astressin 2b. The anti-inflammatory cytokines IL-4 and IL-10 and the pro-inflammatory cytokine TNF-, were measured by ELISA. Results, Urocortin treatment induced a significant and dose-dependent increase of IL-4 and IL-10, whereas it did not affect TNF-, secretion. When incubated in the presence of LPS, Ucn reversed LPS-induced TNF-, release from cultured trophoblast cells, an effect that was blocked by the CRH-R2 selective antagonist, astressin 2b. Conclusion, Urocortin stimulates IL-4 and IL-10 secretion and reverses LPS-induced TNF-, release from trophoblast cells through action on CRH-R2 receptors, suggesting that this peptide may play a possible role as an anti-inflammatory agent. [source] Role of the Neurokinin-1 Receptors in Ejaculation in Anesthetized RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 1 2009Pierre Clement PhD ABSTRACT Introduction., Several lines of evidence indicate a role for substance P in the control of ejaculation, although its mode of action needs to be clarified. Aim., The effects and sites of action of a selective antagonist for the substance P-preferred receptor (neurokinin-1 receptor subtype; NK1) were investigated in a pharmacological model of ejaculation. Methods., Ejaculation was induced in anesthetized rats by intracerebroventricular (icv) delivery of the dopamine D3 receptor preferring agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT). The effects of the selective NK1 antagonist RP67580 on 7-OH-DPAT-induced ejaculation were measured following intraperitoneal (ip), icv, or intrathecal (it) (third lumbar spinal segment; L3) administration. Main Outcome Measures., Intraseminal vesicle pressure (SVP) and electromyogram of the bulbospongiosus muscle (BS) were recorded as physiological markers of emission and expulsion phases of ejaculation, respectively. Results., Upon ip, icv, or it administration, RP67580 significantly reduced the occurrence of ejaculation elicited by 7-OH-DPAT. A mild decrease in the occurrence of SVP and BS responses was observed in rats treated ip with RP67580, whereas only SVP responses were moderately affected following icv or it administration. Conclusion., These results show the multilevel regulation of 7-OH-DPAT-induced ejaculation by NK1 receptors. Clement P, Peeters M, Bernabe J, Laurin M, Alexandre L, and Giuliano F. Role of the neurokinin-1 receptors in ejaculation in anesthetized rats. J Sex Med 2009;6:126,134. [source] ,1D -Adrenoceptors mediate nerve and agonist-evoked contractions in mouse vas deferens: evidence obtained from knockout technologyAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2-3 2008S. Bexis Summary 1 It has been demonstrated that nerve-evoked contractions of the rat vas deferens involve ,1D -adrenoceptors. Definitive evidence for a similar ,1D -adrenoceptor-mediated response in mouse vas deferens has been more difficult to obtain. In this study, we have used ,1D -adrenoceptor knockout (,1D -KO) mice to aid in the pharmacological characterization. 2 Mouse whole vas deferens was stimulated with a single pulse every 5 min. Once a stable response had been obtained, vehicle or antagonist was administered cumulatively at 5-min intervals and a response to stimulation obtained 5 min later. Cumulative concentration-response curves were also obtained for noradrenaline. 3 In vas deferens from ,1D -KO mice, the contractile response to low concentrations of noradrenaline and the contractile response to a single stimulus were significantly reduced as compared to wild type (WT). 4 The ,1D -adrenoceptor selective antagonist, BMY 7378, produced a concentration-dependent inhibition of single pulse-evoked contractions of vas deferens from WT and ,1D -KO mice. BMY 7378 was significantly less potent in inhibiting stimulation-evoked contractions in vas deferens from ,1D -KO mice. 5 It is concluded that ,1D -adrenoceptors mediate a component of nerve- and agonist-evoked contractions of the vas deferens of WT mice. [source] 2-Phenylmelatonin: A Partial Agonist at Enteric Melatonin ReceptorsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2000Maria Grazia Santagostino-Barbone The effect of the melatonin receptor ligand, 2-phenylmelatonin, has been assessed in isolated strips of the guinea-pig proximal colon. 2-Phenylmelatonin (0.01 nM-1 ,M) caused a concentration-dependent contractile response. The potency value (,log EC50) was 9.3±1.0. The maximum effect was 25±4% of that elicited by the maximally effective concentration (0.3 ,M) of 5-HT and 43±3% of that by the maximally effective concentration (10 ,M) of melatonin. When used as an antagonist, 2-phenylmelatonin (0.01 nM and 0.1 nM) concentration-dependently inhibited melatonin-induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2-phenylmelatonin concentrations failed to antagonize melatonin-induced response. Prazosin (0.3 ,M), a selective antagonist of melatonin MT3 sites, antagonized melatonin-induced contractions to an extent similar to that induced by 0.01 nM 2-phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 ,M prazosin and 0.01 nM 2-phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2-Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin-induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist. [source] Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitusBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2009Patricia N. Sidharta WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Urotensin-II (U-II) is one of the most potent vasoconstrictors identified thus far. , Although differences in both U-II blood levels and U-II receptor (UT-receptor) expression have been observed in patients with cardiovascular and cardiorenal disease, the precise function in humans has not been elucidated. , U-II and its receptor have been reported to be involved in glucose metabolism and insulin resistance, which can lead to the development of Type 2 diabetes mellitus. , In rat models of diabetes, palosuran, a selective, potent antagonist of the human UT-receptor, improved several disease markers. WHAT THIS STUDY ADDS , In this study in diabetic patients, the effects of palosuran on insulin secretion and sensitivity were investigated using a hyperglycaemic glucose clamp and a meal tolerance test and daily glucose levels were also studied. , Although no obvious beneficial effect of palosuran in this patient population was observed, the study contributes to providing more insight inro the human U-II/UT-receptor system. AIMS To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study. METHODS After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d., effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake. RESULTS Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of ,1.8 µU ml,1, 95% confidence interval (CI) ,7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean Cmax and AUC, (95% CI) and median tmax (range) in this patient population were 180 ng ml,1 (125, 260), 581 ng·h ml,1 (422, 800) and 3.0 h (0.67, 4.3), respectively. CONCLUSIONS The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes. [source] Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009Carla Ferrada Background and purpose:, Functional interactions between the G protein-coupled dopamine D1 and histamine H3 receptors have been described in the brain. In the present study we investigated the existence of D1,H3 receptor heteromers and their biochemical characteristics. Experimental approach:, D1,H3 receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 receptors. Key results:, Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 receptors can heteromerize. Activation of histamine H3 receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 receptors were co-expressed. Also, dopamine D1 receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co-transfected cells. Furthermore, signalling via each receptor was blocked not only by a selective antagonist but also by an antagonist of the partner receptor. Conclusions and implications:, D1,H3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs -independent and Gi -dependent manner. An antagonist of one of the receptor units in the D1,H3 receptor heteromer can induce conformational changes in the other receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled receptor antagonists. [source] Activation of protein kinase B by the A1 -adenosine receptor in DDT1MF-2 cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000Renée Germack In this study the effect of insulin and A1 -adenosine receptor stimulation on protein kinase B (PKB) activation has been investigated in the hamster vas deferens smooth muscle cell line DDT1MF-2. Increases in PKB phosphorylation were determined by Western blotting using an antibody that detects PKB phosphorylation at Ser473. Insulin, a recognized activator of PKB, stimulated a concentration-dependent increase in PKB phosphorylation in DDT1MF-2 cells (EC50 5±1 pM). The selective A1 -adenosine receptor agonist N6 -cyclopentyladenosine (CPA) stimulated time and concentration-dependent increases in PKB phosphorylation in DDT1MF-2 cells (EC50 1.3±0.5 nM). CPA-mediated increases in PKB phosphorylation were antagonized by the A1 -adenosine receptor selective antagonist 1,3-dipropylcyclopentylxanthine (DPCPX) yielding an apparent KD value of 2.3 nM. Pre-treatment of DDT1MF-2 cells with pertussis toxin (PTX, 100 ng ml,1 for 16 h), to block Gi/Go -dependent pathways, abolished CPA (1 ,M) induced phosphorylation of PKB. In contrast, responses to insulin (100 nM) were resistant to PTX pre-treatment. The phosphatidylinositol 3-kinase (PI-3K) inhibitors wortmannin (IC50 10.3±0.6 nM) and LY 294002 (IC50 10.3±1.2 ,M) attenuated the phosphorylation of PKB elicited by CPA (1 ,M) in a concentration-dependent manner. Wortmannin (30 nM) and LY 294002 (30 ,M) also blocked responses to insulin (100 nM). Removal of extracellular Ca2+ and chelation of intracellular Ca2+ with BAPTA had no significant effect on CPA-induced PKB phosphorylation. Similarly, pretreatment (30 min) with inhibitors of protein kinase C (Ro 31-8220; 10 ,M), tyrosine kinase (genistein; 100 ,M), mitogen-activated protein (MAP) kinase kinase (PD 98059; 50 ,M) and p38 MAPK (SB 203580; 20 ,M) had no significant effect on CPA-induced PKB phosphorylation. In conclusion, these data demonstrate that A1 -adenosine receptor stimulation in DDT1MF-2 cells increases PKB phosphorylation through a PTX and PI-3K-sensitive pathway. British Journal of Pharmacology (2000) 130, 867,874; doi:10.1038/sj.bjp.0703396 [source] An Overview of SR121463, a Selective Non-Peptide Vasopressin V2 Receptor AntagonistCARDIOVASCULAR THERAPEUTICS, Issue 3 2001C. Serradeil-Le Gal ABSTRACT SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V2 receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2 receptors and exhibits a remarkably selective V2 receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2 receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2 receptor mutant. In vitro, SR1 21463 rescued misfolded V2 AVP receptor mutants by increasing cell surface expression and restoring V2 function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2 (or V2 -like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2 receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2 receptors. Pure V2 receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2 receptors (e.g., glaucoma). [source] Prediction of the Three-Dimensional Structure for the Rat Urotensin,II Receptor, and Comparison of the Antagonist Binding Sites and Binding Selectivity between Human and Rat Receptors from Atomistic SimulationsCHEMMEDCHEM, Issue 9 2010Soo-Kyung Kim Dr. Abstract Urotensin-II (U-II) has been shown to be the most potent mammalian vasoconstrictor known. Thus, a U-II antagonist might be of therapeutic value in a number of cardiovascular disorders. However, interspecies variability of several nonpeptidic ligands complicates the interpretation of in vivo studies of such antagonists in preclinical animal disease models. ACT058362 is a selective antagonist for the human U-II receptor (hUT2R) with a reported Kd value of ,4,nM in a molecular binding assay, but it is reported to bind weakly to rat UT2R (rUT2R), with a Kd value of ,1,500,nM. In contrast, the arylsulphonamide SB706375 is a selective antagonist against both hUT2R (Kd=,9,nM) and rUT2R (Kd=,21,nM). To understand the species selectivity of the UT2R, we investigated the binding site of ACT058362 and SB706375 in both hUT2R and rUT2R to explain the dramatically lower (,400-fold) affinity of ACT058362 for rUT2R and the similar affinity (,10,nM) of SB706375 for both UT2Rs. These studies used MembStruk and MSCDock to predict the UT2R structure and the binding site of ACT058362 and SB706375. Based on binding energies, we found two binding modes each with D1303.32 as the crucial anchoring point (Ballesteros,Weinstein numbering given in superscript). We predict that ACT058362 (an aryl,amine,aryl or ANA ligand) binds in the transmembrane (TM) 3456 region, while SB706375 (an aryl,aryl,amine or AAN ligand) binds in the TM 1237 region. These predicted sites explain the known differences in binding of the ANA ligand to rat and human receptors, while explaining the similar binding of the AAN compound to rat and human receptors. Moreover the predictions explain currently available structure,activity relationship (SAR) data. To further validate the predicted binding sites of these ligands in hUT2R and rUT2R, we propose several mutations that would help define the structural origins of differential responses between UT2R of different species, potentially indicating novel UT2R antagonists with cross-species high affinity. [source] | |||||||||||||||||||||||||||||||