Effect of Serotonin (5-HT)₃-Receptor Antagonists YM060, YM 114 (KAE-393), Ondansetron and Granisetron on 5-HT₄ Receptors and Gastric Emptying in Rodents

抄録

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-l-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 pK_i values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pK_i 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 YM 114 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.