COMPARISON OF THE EFFECTS OF TRIMEBUTINE AND YM114 (KAE-393), A NOVEL5-HT3 RECEPTOR ANTAGONIST, ON STRESS-INDUCED DEFECATION

YM114 (KAE-393), olyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hy drochloride, is a derivative of YM060, a potent 5-HT3 receptor antagon ist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stres s, 5-HT and thyrotropin-releasing hormone (TRH), and compared them wit h the effect of trimebutine. YM114 dose dependently inhibited the redu ction in heart rate induced by 5-HT (30 mug/kg i.v.) in rats (ED50 = 0 .31 mug/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced brad ycardia, but 1350 times less potent than the R-form. YM114 and its S-f orm inhibited [H-3]GR65630 binding to N1E-115 cell membranes in a conc entration-dependent manner with K(i) values of 0.341 and 616 nM, respe ctively, showing the isomeric activity ratio (R-/S-form) of YM114 to b e much greater (1800). YM114 antagonized 5-HT-induced depolarization o f the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) fai led to inhibit 5-HT-induced bradycardia, implying that it does not pos sess 5-HT3 receptor antagonistic activity. YM114 significantly and dos e dependently prevented restraint stress-, 5-HT- and TRH-induced incre ases in fecal pellet output, and restraint stress- and 5-HT-induced di arrhea in rats and mice (ED50=6.9,72.5,154.6,9.7 and 52.4 mug/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-i nduced diarrhea (ED50 = 29.4 and 87.3 mg/ kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fe cal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 r eceptor antagonist with much greater protective effects against stress -induced defecation than trimebutine.