Pharmacological Properties of KF18259, a Novel 5-HT₃-Receptor Antagonist, in Rats: Inhibition of the Distal Colonic Function

Abstract

We investigated the effects of KF18259 (endo-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-isobutyl-2-oxo-1, 2-dihydro-4-quinolinecarboxylate hydrochloride), a novel 5-HT₃-receptor antagonist, in a variety of rat models, which are assumed to be mediated via 5-HT₃ receptors, in comparison with those of YM060 ((R)-5-[(1-methyl-3-indolyl)carbonyl]-4, 5, 6, 7-tetrahydro-1H-benzimidazole hydrochloride), granisetron and ondansetron. KF18259 inhibited wrap-restraint stress-induced defecation. The doses of KF 18259 to inhibit wrap-restraint stress-induced defecation were lower than those to inhibit the 5-HT-induced von Bezold-Jarisch reflex and the cisplatin-induced slowing of gastric emptying. In contrast, the doses of YM060, granisetron and ondansetron to inhibit these three responses were similar. Moreover, KF18259 inhibited the wrap-restraint stress-induced propulsive motility of the proximal and distal colon. The effect of KF18259 on the distal colon was as potent as that on defecation and was more potent than that on the proximal colon. These results indicate that KF18259 potently inhibits the distal colonic function. KF18259 may be a useful tool for the discrimination of the 5-HT₃-receptors located on the distal colon and other tissues.