PHARMACOLOGICAL CHARACTERIZATION OF RS-25259-197, A NOVEL AND SELECTIVE 5-HT3 RECEPTOR ANTAGONIST, IN-VIVO

1 The pharmacological effects in vivo, of RS 25259-197, a selective 5-HT3 receptor antagonist, have been investigated. 2 In anaesthetized rats, RS 25259-197, administered by the intravenous, intraduodenal or transdermal route, dose-dependently inhibited the von Bezold-Jarisch reflex induced by 2-methyl 5-HT (ID50 = 0.04 mu g kg(-1), i.v., 3.2 mu g kg(-1), i.d. and 32.8 mu g per chamber, respectively). In this regard, when administered intraduodenally, RS 25259-197 was more potent and exhibited a longer duration of action than either ondansetron or granisetron. 3 In conscious ferrets, RS 25259-197, administered intravenously or orally, dose-dependently inhibited emesis induced by cisplatin. The ID50 estimates of RS 25259-197 were 1.1 mu g kg(-1), i.v. and 3.2 mu g kg(-1), p.o. In this respect, RS 25259-197 was more potent than ondansetron and equipotent with granisetron. 4 In conscious dogs, RS 25259-197, administered intravenously or orally, dose-dependently inhibited emesis induced by cisplatin (ID50 = 1.9 mu g kg(-1), i.v. and 8.5 mu g kg(-1), p.o.), dacarbazine (ID50 = 4.1 mu g kg(-1), i.v, and 9.7 mu g kg(-1), p.o.), actinomycin D (ID50 = 4.9 mu g kg(-1), i.v. and 2.5 mu g kg(-1), p.o.) and mechlorethamine (ID50 = 4.4 mu g kg(-1), i.v. and 3.0 mu g kg(-1), p.o.). Against each of the emetogenic agents, RS 25259-197 was very much more potent than ondansetron. When tested at equi-effective intravenous doses against cisplatin-induced emesis in dogs, RS 25259-197 had a longer duration of anti-emetic activity (7 h) than ondansetron (4 h). At doses up to and including 1000 mu g kg(-1), p.o., neither RS 25259-197 nor ondansetron was capable of inhibiting apomorphine-induced emesis. 5 At doses up to 1000 mu g kg(-1), i.v., RS 25259-197 produced no meaningful haemodynamic changes in anaesthetized dogs. 6 In summary, RS 25259-197 is a novel, highly potent and orally active 5-HT3 receptor antagonist in vivo. With respect to its anti-emetic activity, RS 25259-197 appears to be a significant improvement over ondansetron in terms of potency and duration of action.