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

(R)-5-[(1-Methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (YM060) is a structurally novel, extremely potent, and highly selective serotonin (5HT)3 receptor antagonist. Its 5HT3 receptor blocking properties were compared with those of its enantiomer (S-form), granisetron and ondansetron, in the isolated distal colon of the guinea pig. YM060 competitively antagonized 5HT- and 2-methyl-5HT-induced contraction of the colon, with pA2 values of 8.71 +/- 0.09 (n = 12) and 8.69 +/- 0.06 (n = 9), respectively. Its antagonistic activity was approximately 200, 5 and 50 times more potent than those of the S-form (pA2 = 6.33 +/- 0.06, n = 9 against 5HT; 6.47 +/- 0.1, n = 9 against 2-methyl-5HT), granisetron (pA2 = 8.03 +/- 0.07, n = 9; 8.02 +/- 0.04, n = 9), and ondansetron (pA2 = 7.02 +/- 0.08, n = 9; 6.98 +/- 0.02, n = 9), respectively. Each pA2 value was constant and the isomeric activity ratio (R-form/S-form) was constant irrespective of the agonist used, suggesting that each drug acted on the same 5HT3 receptor. YM060 failed to antagonize contractions induced by 5HT in the saphenous vein of the dog (5HT1-like receptor) or in the aorta of the rabbit (5HT2 receptor. YM060 has a low affinity for alpha-1 (rabbit aorta; pA2 = 5.08 +/- 0.07, n = 8) and alpha-2 (guinea pig ileum; pA2 = 5.61 +/- 0.09, n = 11) adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacologic profile of (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride (YM060), a potent and selective 5-hydroxytryptamine3 receptor antagonist, and its enantiomer in the isolated tissue. 165 16

YM060, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, is a new serotonin (5HT)3-receptor antagonist. We examined the effects of YM060 on chemotherapeutic agent-, apomorphine- and copper sulfate-induced emesis. Intravenous YM060 potently prevented cisplatin (10 mg/kg, i.v.)-induced emesis with ED50 values of 0.06 (0.05-0.07) micrograms/kg, i.v. in ferrets. Based on the ED50 values, YM060 was 300, 20 and 100 times more potent than ondansetron, granisetron and the S-isomer of YM060, respectively. The relative potencies of these drugs described above were similar to those in the previously reported 5HT3-receptor antagonism. YM060 given orally also potently inhibited cisplatin (10 mg/kg, i.p.)- and cyclophosphamide (200 mg/kg, i.p.)-induced emesis in ferrets with ED50 values of 0.1 (0.09-0.11) and 0.02 (0.16-0.27) micrograms/kg, p.o., respectively. All tested 5HT3-receptor antagonists including YM060 failed to prevent apomorphine (0.1 mg/kg, s.c.)-induced emesis in dogs and copper sulfate (1%, 10 ml, p.o.)-induced emesis in ferrets. Our data indicate that YM060 is a highly potent inhibitor of chemotherapeutic agent-induced emesis and that the antiemetic effect of YM060 may be depend on 5HT3-receptor antagonism.
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PMID:Antiemetic effects of YM060, a potent and selective serotonin (5HT)3-receptor antagonist, in ferrets and dogs. 181 64

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

We evaluated the inhibitory effects of YM060 [(R)-5-[(1-methyl-1H-indol- 3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride] and YM114 (KAE-393) [(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole monohydrochloride] on the von Bezold-Jarisch reflex (BJR) induced by 2-methyl-5-HT, a selective serotonin (5-HT)3-receptor agonist; veratridine, which stimulates chemoreceptors and baroreceptors; and electrical stimulation of vagal efferent nerves in anesthetized rats. Results were compared with those of ondansetron and granisetron. 2-Methyl- 5-HT (5-160 micrograms/kg, i.v.) and veratridine (100-200 micrograms/kg, i.v.) dose-dependently decreased the heart rate (BJR). YM060, YM114, ondansetron and granisetron dose-dependently inhibited 2-methyl-5-HT (40 micrograms/kg, i.v.)-induced BJR, with ID50 values of 0.012, 0.060, 0.97 and 0.15 microgram/kg, i.v., respectively. Their 5-HT3 receptor blocking potencies against 2-methyl-5-HT-induced BJR were largely consistent with those against 5-HT-induced BJR. In contrast, higher doses (100 micrograms/kg, i.v.) of YM060, YM114, ondansetron and granisetron did not inhibit veratridine (150 micrograms/kg, i.v.)-induced BJR. Atropine (300 micrograms/kg, i.v.) abolished bradycardia induced by electrical stimulation of vagal efferent nerves, whereas YM060, YM114, ondansetron and granisetron had no effect at a dose of 1000 micrograms/kg, i.v. 5-HT (0.625-5.0 micrograms) injected into the left ventricle also caused a dose-dependent decrease in heart rate, an effect that was abolished by YM060 (0.1 microgram/kg, i.v.), atropine (100 micrograms/kg, i.v.) and vagotomy. These results suggest that YM060 and YM114 are highly potent and selective 5-HT3-receptor antagonists that do not affect veratridine- or electrical stimulation-induced bradycardia in anesthetized rats. They also suggest that 5-HT-induced BJR in anesthetized rats originates from 5-HT3 receptors located on the endings of vagal afferent nerves in the heart.
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PMID:Characteristics of inhibitory effects of serotonin (5-HT)3-receptor antagonists, YM060 and YM114 (KAE-393), on the von Bezold-Jarisch reflex induced by 2-Methyl-5-HT, veratridine and electrical stimulation of vagus nerves in anesthetized rats. 878 38

We characterized [3H]YM060 ([methyl-3H]-(-)-(R)-5-[(methyl-1H- indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride) binding in membrane homogenates prepared from three different rat tissues (cerebral cortex, ileum and colon), and compared the binding characteristics between the native and cloned rat 5-HT3 receptors. The dissociation constant (Kd) of [3H]YM060 was similar in all membranes. In competition studies, the affinity of 5-HT3 receptor agonists and antagonists was similar between the native and the cloned rat 5-HT3 receptors. In conclusion, intra-species difference of 5-HT3 receptor was not observed in rats and pharmacological properties of the cloned rat 5-HT3 receptor were nearly identical to that of the native rat 5-HT3 receptor.
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PMID:Comparison of [3H]YM060 binding to native and cloned rat 5-HT3 receptors. 883 61

The R- and S-enantiomers of the 4,5,6,7-tetrahydro-1H-benzimidazole derivatives 3-8 were prepared by optical resolution. Each R-isomer, except for 3, was almost two orders of magnitude more potent than its S-isomer as a 5-hydroxytrptamine (5-HT3) receptor antagonist, as judged from they effect on the von Bezold-Jarisch reflex (B. J. reflex) in rats, the contraction of isolated guinea-pig colon and the receptor-binding affinity. The (--)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] derivative 6R.HCl (ramosetron = YM060) and (--)-(R)-5-[(1-indolinyl)carbonyl] derivative 4R.HCl (YM114 = KAE-393) given p.o. were hundreds of times more potent than 1 (ondansetron) and 2 (granisetron) in their inhibitory effects on cisplatin-induced emesis in ferrets and restraint stress-induced increases in fecal pellet output in rats. Three-dimensional molecular modeling studies suggested that the 'chiral selection' of the enantiomers might be influenced by the steric repulsion between the aromatic ring part and the conformationally restricted 4,5,6,7-tetrahydro-1H-benzimidazole ring in "equatorial-twist" conformation. In our pharmacophore model for the 5-HT3 receptor antagonist, a basic center exists at the left side of the aromatic-carbonyl plane when viewing from the aromatic part with the carbonyl oxygen atom upwards, whereas the "handedness" is ambiguous in the previously proposed model.
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PMID:Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. III. Pharmacological evaluations and molecular modeling studies of optically active 4,5,6,7-tetrahydro-1H-benzimidazole derivatives. 885 65

In physicochemical and pharmacokinetic evaluations of (--)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride 1 (YM060: ramosetron), which is a highly potent 5-hydroxytryptamine(-HT3) receptor antagonist, 4-hydroxy-6-[(1-methyl-1H-indol-3-yl) carbonyl]4,5,6,7-tetrahydro-1H-benzimidazole 2 was identified as a degradation product and metabolite of 1. The (--)-(4R,6S)-isomer 2 was synthesized from the diketone derivative 3, via the stereoselective reduction of 3 followed by the stereocontrolled epimerization of the (--)-(4S,6S)-isomer 10, the epimer of 2. The stereochemistry of 2 and 10 was determined by NMR and HPLC studies. Compounds 2 and 10 were found to be potent 5-HT3 receptor antagonists, like 1. Among the other oxidation products, the diketone derivatives 3 and 7 and the dihydroxylated derivative 4 retained antagonistic activity similar to that of ondansetron. This is of interest, because they do not possess the amine group which is known to be necessary for high affinity to the 5-HT3 receptor.
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PMID:Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. IV. Synthesis and pharmacological evaluation of the oxidation products of (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (YM060: ramosetron). 885 66

We investigated the participation of cholinergic and tachykininergic mechanisms in 5-hydroxytryptamine (5-HT)-induced contraction via 5-HT3 receptors in longitudinal and circular muscle of guinea-pig isolated distal colon. 5-HT produced concentration-dependent contractile responses in longitudinal and circular muscle. The 5-HT3 receptor antagonists ramosetron (YM060) ((R)-5-[(1-methyl-3-indolyl) carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride), YM114 (KAE-393) ((R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole hydrochloride), ondansetron and granisetron produced a concentration-dependent shift to the right of the 5-HT concentration-response curves in both muscle. However, methysergide and GR113808 had no effect on 5-HT-induced contraction. In the longitudinal muscle, atropine concentration-dependently inhibited 5-HT-induced contraction, and tetrodotoxin abolished it. (+/-)-CP96,345 attenuated the contractile response to 5-HT, but (+/-)-SR48,968 had no effect on it. In the presence of atropine, (+/-)-CP96,345 completely blocked 5-HT-induced contraction. In the circular muscle, atropine had no effect on the contractile response to 5-HT, whereas tetrodotoxin completely suppressed it. The contractile response elicited by 5-HT in the circular muscle was not inhibited by either (+/-)-CP96,345, (+/-)-SR48,968, devazepide, L-365,260 or indomethacin. It is suggested that 5-HT acts via 5-HT3 receptors to release acetylcholine and substance P, which in turn are responsible for contraction of the longitudinal muscle. In the circular muscle, as in the longitudinal muscle, 5-HT-induced contraction is mediated by the 5-HT3 receptor. Unlike the case in longitudinal muscle, however, this contraction involves neither cholinergic nor tachykininergic transmission. It is also suggested that neither cholecystokinin (CCK) nor prostaglandins participate in 5-HT3 receptor-mediated contraction in circular muscle.
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PMID:Investigation of 5-HT3 receptor-mediated contraction in guinea-pig distal colon. 899 21