EFFECT OF GK-128 THYLIMIDAZOL-1-YL)METHYL]BENZO[F]THIOCHROMEN-1-ONE MONOHYDROCHLORIDE HEMIHYDRATE], A SELECTIVE 5-HYDROXYTRYPTAMINE(3) RECEPTOR ANTAGONIST, ON COLONIC FUNCTION IN RATS

We investigated the effects of various selective 5-hydroxytryptamine ( 5-HT)(3) receptor antagonists, including GK-128 [2-[(2-methylimidazol- 1 -yl)methyl]benzo[f]thiochromen-1-one monohydrochloride hemihydrate], on colonic function. In conscious rats, 5-HT and a 5-HT3 receptor ago nist, 2-methyl-5-HT, dose-dependently increased fecal pellet output, b ut another 5-HT3 receptor agonist, m-chlorophenylbiguanide, did not af fect output, The selective 5-HT3 receptor antagonists GK-128, graniset ron, ramosetron, azasetron and ondansetron depressed the increase in f ecal pellet output caused by 2-methyl-5-HT and by wrap-restraint stres s. However, the rank order of potency of antagonists in the two defeca tion models was not consistent with that for the von Bezold-Jarisch re flex. Although granisetron and ramosetron dose-dependently reduced the spontaneous excretion of fecal pellets, GK-128 did not affect it. The se results suggest that GK-128 may be used for the treatment of stress -induced gastrointestinal dysfunction. Furthermore, the present result s suggest that the 5-HT3 receptor involved in colonic motility may be different from the classically defined 5-HT3 receptor and/or that the regulation of colonic motility mediated by 5-HT3 receptors during stre ss may be different from normal physiological conditions.