Jpn. J. Pharmacol. 69, 205-214 (1995)

Effect of Serotonin (5-HT)3-Receptor Antagonists YM060, YM114 (KAE-393), Ondansetron and Granisetron on 5-HT4 Receptors and Gastric Emptying in Rodents

Keiji Miyata, Mayumi Yamano, Takeshi Kamato and Shinobu Akuzawa

Neuroscience and Gastrointestinal Research Laboratories, Institute for Drug Discovery, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan

Abstract: We investigated the effects of YM060 {(R)-5-[(1-methyl-3-indolyl)carbonyl]- 4,5,6,7-tetra-hydro-1H-benzimidazole 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 pA4 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.

Keywords: YM060, YM114 (KAE-393), 5-HT4 receptor, Gastric emptying

Copyright© The Japanese Pharmacological Society 1995

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