Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro.

Abstract We investigated the in vitro pharmacological profile of YM-31636 (2-(1 H -imidazol-4-ylmethyl)-8 H -indeno[1,2- d ]thiazole monofumarate). In cloned human 5-HT 3A receptors, YM-31636 had a p K i value of 9.67 vs. ramosetron and p K i values for other 5-HT 3 receptor agonists were less than 7. YM-31636 showed very low affinities for other receptors. YM-31636 induced contraction of isolated guinea pig distal colon. The intrinsic activity was approximately 0.90 compared with 5-hydroxytryptamine's (5-HT) 1.0, and the potency was 26 times greater than that of 5-HT. YM-31636 increased short-circuit current ( I sc ) in the isolated guinea pig distal colon. In this case, the relative intrinsic activity was approximately 0.19. In isolated guinea pig right atrium, YM-31636 induced tachycardia with the relative intrinsic activity of approximately 0.23. All these effects of YM-31636 were antagonized by ramosetron, a selective 5-HT 3 receptor antagonist. These results suggest that YM-31636 is a potent and selective 5-HT 3 receptor agonist, preferentially acting on the contraction of the colon.