Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A putative 5-HT4 receptor-mediated depolarization of the rat isolated vagus nerve has been studied using a grease-gap extracellular recording technique. Ondansetron (1 microM) was used to block the predominant 5-HT3 receptor mediated depolarization in this preparation and the effects of the 5-HT4 receptor antagonists DAU 6285 (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-2,3-dihydro-6-methoxy-2-oxo-1H-benzimidazole-1- carboxylate HCl); 0.3, 1.0 or 3.0 microM and SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)-ethyl ester HCl); 0.1, 0.3 or 1.0 microM were studied on the residual, ondansetron-resistant, component of the response. The effects of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) and of forskolin on the ondansetron-resistant response were also studied. Both DAU 6285 and SDZ 205-557 acted as competitive antagonists of the ondansetron-resistant response to 5-HT with pA2 values of 6.8 (6.7-7.1, n = 12) and 7.1 (6.9-7.5, n = 12) respectively. The vagus nerve was depolarized by IBMX (100 microM) or forskolin (10 microM), the effects being similar to the maximum response to 5-HT. In the presence of IBMX (100 microM) or forskolin (10 microM) the ondansetron-resistant component of the response to 5-HT was enhanced and the 5-HT3 receptor-mediated component reduced. These results with DAU 6285 and SDZ 205-557 are consistent with a 5-HT4 receptor-mediated mechanism of the ondansetron-resistant depolarizing response to 5-HT.
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PMID:Further characterization of the putative 5-HT4 receptor mediating depolarization of the rat isolated vagus nerve. 747 28

We used conventional intracellular recording methods to examine the effects of YM060 [(-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole monohydrochloride), a novel 5-HT3 receptor antagonist, on 5-hydroxytryptamine (5-HT, serotonin)-evoked fast membrane depolarization in myenteric neurons of the guinea pig distal colon, and compared its potency to that of other 5-HT3 receptor antagonists. Microapplication of 5-HT from fine-tipped pipettes evoked both fast and slowly activating depolarizing responses in 78% and 40% of colonic myenteric neurons, respectively. The selective 5-HT3 receptor agonist 2-methyl-5-HT applied with short pressure pulses (100-300 ms) mimicked the fast but not the slow response. The 5-HT3 receptor antagonists YM060, granisetron and ondansetron suppressed the 5-HT-evoked fast response in 98% of colonic myenteric neurons in a concentration-dependent manner with pIC50 values of 8.62, 7.77 and 6.90, respectively. Methysergide and GR113808 did not affect the fast responses at concentrations sufficient to block 5-HT1, 5-HT2 and 5-HT4 receptors, respectively. YM060 did not affect the slowly activating response to 5-HT or any other electrophysiological parameter of the neurons including resting membrane potential, input resistance and the amplitude of action potentials evoked by injection of depolarizing current. Stimulus-evoked fast excitatory postsynaptic potentials were unchanged by YM060 at concentrations up to 10(-8) M, excluding any possible local anesthetic or anticholinergic effects of YM060. The results confirm that the fast component of the two depolarizing responses to 5-HT in colonic myenteric neurons is mediated by 5-HT3 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory effect of YM060 on 5-HT3 receptor-mediated depolarization in colonic myenteric neurons of the guinea pig. 749 99

We assessed the 5-HT3-receptor antagonist effects of 4,5,6,7-1H-benzimidazole compounds which are derivatives of YM060, a potent and selective 5-HT3-receptor antagonist, in isolated guinea pig colon. YM114 (KAE-393), YM-26103-2, YM-26308-2 (3 x 10(-9) to 3 x 10(-8) M) produced concentration-dependent shifts to the right of the dose-response curves for both 5-HT and 2-methyl-5-HT (2-Me-5-HT). YM114 (pA2 = 9.08 against 5-HT, pA2 = 8.88 against 2-Me-5-HT), YM-26103-2 (pA2 = 8.27 against 5-HT, pA2 = 8.19 against 2-Me-5-HT), and YM-26308-2 (pA2 = 8.58 against 5-HT, pA2 = 8.4 against 2-Me-5-HT) showed similar pA2 values irrespective of the agonist used, suggesting that they have 5-HT3-receptor blocking activity irrespective of the N-position at the aromatic ring. Since these compounds have an asymmetric center, their enantiomers exist. The S-isomers were one to three orders of magnitude less potent than the respective R-isomer compounds, indicating that the stereochemical configuration of 4,5,6,7-tetrahydro-1H-benzimidazoles is an important determinant of their affinity for 5-HT3 receptors. These results suggest that the highly potent 5-HT3 receptor antagonism and high selectivity for 5-HT3 receptors of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives are conserved irrespective of the position of the nitrogen atom in the aromatic ring and that 5-HT3 receptors favor the R-isometric conformation of these compounds.
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PMID:Studies on serotonin (5-HT)3-receptor antagonist effects of enantiomers of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives. 763 36

YM114 (KAE-393), (R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole hydrochloride, is a derivative of YM060, a potent 5-HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depolarization of the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) failed to inhibit 5-HT-induced bradycardia, implying that it does not possess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint stress-, 5-HT- and TRH-induced increases in fecal pellet output, and restraint stress- and 5-HT-induced diarrhea in rats and mice (ED50 = 6.9, 72.5, 154.6, 9.7 and 52.4 micrograms/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine.
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PMID:Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation. 811 88

The binding of [3H]endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)- 2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride ([3H]BIMU-1) a benzimidazolone with high affinity for 5-hydroxytryptamine (5-HT)3 and 4 5-HT3 and 5-HT4 receptors, was characterized in NG-108 cells and guinea pig hippocampus. Specific, heat-sensitive, binding of [3H]BIMU-1 was detected in both NG-108 cells and guinea pig hippocampus. In NG-108 cell membranes, a portion of the specific binding was displaced by 5-HT3 receptor ligands with affinities and specificity consistent with the labeling of 5-HT3 receptors. The residual specific binding was insensitive to serotonin (Ki > 1 mM) but was displaced by haloperidol (Ki of 50 nM). In guinea pig hippocampal membranes [3H]BIMU-1 binding was insensitive to serotonin but was displaced by haloperidol, and 1,3-di-o-tolyl-guanidine with affinities appropriate for the labeling of a sigma binding site (Ki of 6.3 and 31 nM, respectively). The affinity profile of ligands displacing [3H] BIMU-1 binding in guinea pig hippocampus was consistent with the selective labeling of a sigma-2 binding site because the sigma-1 selective benzomorphans, (+)-pentazocine and (+)-N-allylnormetazocine, only weakly displaced the binding (Ki greater than 1 microM). The affinity of BIMU-1 for sigma-2 binding sites (Ki = 32 nM) was 200-fold greater than that for sigma-1 binding sites (Ki = 6.3 microM), dopamine (D1 and D2), other serotonin (5-HT1A, 5-HT2A, 5-HT2C) and muscarinic (M1, M2, M3 and M4) receptors (Ki > 10 microM). The distribution of haloperidol-sensitive [3H]BIMU-1 binding was also consistent with the labeling of sigma-2 binding sites. These data suggest that [3H]BIMU-1 selectively labels sigma-2 binding sites in guinea pig hippocampus. [3H]BIMU-1, under appropriate experimental conditions, is thus the first sigma-2 binding site radioligand to be characterized.
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PMID:[3H]BIMU-1, a 5-hydroxytryptamine3 receptor ligand in NG-108 cells, selectively labels sigma-2 binding sites in guinea pig hippocampus. 824 71

The binding properties of a new radioligand, [methyl-3H]-(-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole monohydrochloride ([3H]YM060), were studied in membranes of the rat cerebral cortex. [3H]YM060 rapidly associated with its binding sites in membranes and reversibly dissociated. Saturation analysis revealed that the specific binding of [3H]YM060 was saturable and non-specific binding was low. Scatchard analysis yielded a linear plot, suggesting a single population of binding sites with a dissociation constant (Kd) of 8.4 +/- 0.2 pM (n = 3) and the kinetic Kd determined from the association constant (K+1) and the dissociation rate constant (K-1) was similar. The maximum number of binding sites (Bmax) was 37.0 +/- 0.8 fmol/mg protein (n = 3). [3H]YM060 binding was potently and stereospecifically inhibited by serotonin (5-HT)3 receptor agonists and antagonists. Other 5-HT receptor ligands such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), methysergide and ketanserin were inactive to inhibit specific binding at 10(-4) M. These results suggest that [3H]YM060 is a highly potent and selective 5-HT3 receptor radioligand and will be useful in the further analysis of 5-HT3 receptors.
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PMID:Characterization of [3H]YM060, a potent and selective 5-HT3 receptor radioligand, in the cerebral cortex of rats. 856 14

The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl-methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F-0930-RS2), a new 5-HT3 receptor antagonist, on ipecacuanha-induced nausea and vomiting. The ipecacuanha model of emesis has been used to test the anti-emetic activity of several different 5-HT3 antagonists and the anti-emetic doses that were effective in the ipecacuanha model have been found to correlate well with the clinically effective doses. Study 1 investigated oral doses of lerisetron from 4 mg to 40 mg. Study 2 evaluated the duration of effect of a single dose of 20 mg oral lerisetron. Study 3 evaluated intravenous doses of 18 mg and 12 mg lerisetron. In Study 1, the 40 mg dose of oral lerisetron inhibited emesis in all test subjects. The percentage of subjects who experienced an emetic episode increased as the dose of lerisetron decreased. At the lowest dose level tested five of six subjects had an emetic episode compared with four out of five in the placebo group. In Study 2, 20 mg oral lerisetron was effective up to 12 h after administration. When ipecacuanha was administered at 18 h post-dose three of seven subjects had an emetic episode and at 24 h post-dose the incidence of emesis was similar to the placebo treatment groups in the previous study. Study 3 demonstrated the effectiveness of intravenous doses of lerisetron. The 18 mg intravenous dose reduced the number of patients experiencing emetic episodes by 75% compared with placebo, doses below 12 mg i.v. were not evaluated because of the reduced efficacy of the compound at this dose level. In conclusion, lerisetron has been shown to be effective in the treatment of ipecacuanha-induced nausea and vomiting at intravenous doses of 18 mg and at oral doses of 20 mg for up to 12 hours.
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PMID:Effects of lerisetron, a new 5-HT3 receptor antagonist, on ipecacuanha-induced emesis in healthy volunteers. 1240 84