Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome

We examined the pharmacological profile of ramosetron, a 5-HT3-receptor antagonist for irritable bowel syndrome with diarrhea, comparing it with those of other 5-HT3-receptor antagonists, alosetron and cilansetron, and the anti-diarrheal agent loperamide. Ramosetron showed high affinity for cloned human and rat 5-HT3 receptors, with K-i values of 0.091 +/- 0.014 and 0.22 +/- 0.051 nmol/L, respectively, while its affinities for other receptors, transporters, ion channels, and enzymes were negligible. Dissociation of ramosetron from the human 5-HT3 receptor was extremely Slow (t(1/2) = 560 min), while alosetron (t(1/2) = 180 min) and cilansetron (t(1/2) = 88 min) dissociated relatively rapidly. Ramosetron competitively inhibited 5-HT-induced contraction of isolated guinea-pig colon, with pA(2) values of 8.6 (8.5 - 9.0). Ramosetron given orally also dose-dependently inhibited the von Bezold-Jarisch reflex in rats, with an ED50 value of 1.2 (0.93 - 1.6) mu g/kg. In addition, oral ramosetron dose-dependently inhibited restraint stress-induced defecation in rats, with an ED50 value of 0.62 (0.17 - 1.2) mu g/kg. In all of these experiments, the potencies of ramosetron were greater than those of alosetron, cilansetron, or loperamide. These results indicate that ramosetron is a highly potent and selective 5-HT3-receptor antagonist, with beneficial effects against stress-induced abnormal defecation in rats.