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