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

ABSTRACT-We investigated the effects of YM060 {(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-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-4-piperidin-yl]methyl 1-methyl-lH-indole-3-carboxylate} in guinea pig striatum, with pK; values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pK; 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. Keywords: YM060, YM114 (KAE-393), 5-HT4 receptor, Gastric emptyingThe use of cisplatin in the treatment of cancer is usually accompanied by the side effects of severe nausea and vomiting. Recently, a number of compounds that inhibit these side effects have been developed. These compounds all act via inhibition of 5-HT3 receptors. YM060 and YM114 (KAE-393) are 4,5,6,7-tetrahydrobenzimidazole derivatives. These compounds have been reported to be potent and selective 5-HT3-receptor antagonists of 5-HTinduced von Bezold-Jarisch reflex in rats (1, 2), contraction of the guinea pig colon (3, 4) and depolarization of the rabbit nodose ganglion (2, 5).To date, a number of 5-HT3-receptor antagonists have been synthesized. Among these, tropisetron (6), cisapride (7), zacopride (8), ondansetron (9) and renzapride (10) have been reported to possess gastroprokinetic activities in rats or guinea pigs. Compounds that block the 5-HT3 receptor are therefore suggested to increase the rate of gastric emptying.Recent studies have revealed that the peripheral 5-HT4-receptor subtype is involved in the control of gastrointestinal motility through the release of acetylcholine (11-13) and that 5-HT4-receptor agonists facilitate gastric emptying (14, 1...

Effects of gastroprokinetic agents on gastroparesis in streptozotocin-induced diabetic rats

“…The selective 5-HT 3 receptor antagonists ramosetron, YM114, granisetron and ondansetron, and the substiuted benzamides (5-HT 4 receptor agonist/5-HT 3 receptor antagonists) cisapride, mosapride and SC-53116 dose-dependently enhanced the gastric emptying in normal rats. These results are quite consistent with those of other reports (Linnik et al 1991;Turconi et al 1991;Ku et al 1993;Miyata et al 1995). These gastroprokinetic agents also improved the delay of solid gastric emptying in STZtreated rats, but higher doses were needed than those which were effective in normal rats.…”

“…The gastric emptying experiments were performed from 1:00 p.m. according to the method of Miyata et al (1995). One hundred glass beads (1 mm in diameter) were orally given a Nelaton's catheter with 1 ml of water.…”

“…Subdiaphragmatic vagotomized rats were also employed as a vagal neuropathy model to examine whether neuropathy affected gastric emptying. Since substituted benzamides and the selective 5-HT 3 receptor antagonists elicited gastroprokinetic responses in normal rats (Linnik et al 1991;Turconi et al 1991;Ku et al 1993;Miyata et al 1995), the effects of these gastroprokinetic agents on STZ-and vagotomy-induced gastroparesis were also examined in rats, and the results were compared with those obtained in normal rats.…”

5-HT3receptors participate in CCK-induced suppression of food intake by delaying gastric emptying

“…Some studies using acute systemic administration of ondansetron showed an inhibition of gastric emptying (17), whereas others showed an increase in gastric emptying (27,39). A number of factors may account for this discrepancy.…”

“…For example, Miyata et. al (39) and Ito et al (27) examined gastric emptying of glass powder/ beads and found that systemic administration of ondansetron at low doses (0.01-0.1 mg/kg) increased gastric emptying. On the other hand, Forster and Dockray (17) showed that peripheral administration of similar low doses of ondansetron enhanced peptone-induced suppression of gastric emptying.…”