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

We investigated the in vitro pharmacological profile of YM-31636 (2-(1 H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate). In cloned human 5-HT3A receptors, YM-31636 had a p K-i value of 9.67 vs, ramosetron and p K-i values for other 5-HT3 receptor agonists were less than 7. YM-31636 showed very low affinities far 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 gig 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, receptor antagonist. These results suggest that YM-31636 is a potent and selective S-HT3 receptor agonist, preferentially acting on the contraction of the colon. (C) 2000 Elsevier Science B.V. All rights reserved.