title: Effect of serotonin (5-HT)3-receptor antagonists YM060, YM114 (KAE-393), ondansetron and granisetron on 5-HT4 receptors and gastric emptying in rodents.
abstract: We investigated the effects of YM060 [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride] and YM114 (KAE-393) [(R)-5-[(2,3-dihydro-1-indolyl)-carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride] on 5-HT4 receptors and gastric emptying in normal and cisplatin-treated rats and compared results with those for ondansetron and granisetron. YM060, YM114, ondansetron and granisetron dose-dependently inhibited the specific binding of [3H]-GR113808 ([[1-[(2-methylsulphonyl)amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1H-indole-3-carboxylate) in guinea pig striatum, with pKi values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pKi values reported in 5-HT3-receptor binding of [3H]GR65630 to rat cortical membranes, the affinity of YM060, YM114, ondansetron and granisetron for 5-HT4 receptors was approximately 5, 5, 3.5 and 3.5 log units lower than that for 5-HT3 receptors, respectively. In the guinea pig longitudinal muscle with myenteric plexus and rat esophageal tunica muscularis mucosae, YM060 and YM114 showed neither 5-HT4-agonistic nor antagonistic properties. Although ondansetron produced concentration-dependent increases in the magnitude of the twitch response in longitudinal muscle, it did not possess 5-HT3- and 5-HT4-agonistic activity. Granisetron antagonized 5-HT-induced relaxation of the rat esophagus with an apparent pA2 value of 5.39. Intravenous YM060, YM114, ondansetron and granisetron significantly enhanced gastric emptying of glass beads and improved cisplatin-induced slowing of gastric emptying in rats. These results indicate that the selectivity of YM060 and YM114 for 5-HT3 receptors is higher than that of ondansetron and granisetron and that these 5-HT3 antagonists have gastroprokinetic activity in normal and cisplatin-treated rats without affecting 5-HT4 receptors.
authors.affiliation: Neuroscience Research Laboratory, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: M
authors.initials: M
authors.lastname: Yamano
authors.forename: T
authors.initials: T
authors.lastname: Kamato
authors.forename: S
authors.initials: S
authors.lastname: Akuzawa
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects*; D017829:Granisetron / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D017294:Ondansetron / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D002945:Cisplatin; D017829:Granisetron; D017294:Ondansetron; D012702:Serotonin Antagonists; C085986:YM 114; C071315:ramosetron