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 ra ts, RS 25259-197, administered by the intravenous, intraduodenal or tr ansdermal route, dose-dependently inhibited the von Bezold-Jarisch ref lex 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 e xhibited a longer duration of action than either ondansetron or granis etron. 3 In conscious ferrets, RS 25259-197, administered intravenousl y or orally, dose-dependently inhibited emesis induced by cisplatin. T he ID50 estimates of RS 25259-197 were 1.1 mu g kg(-1), i.v. and 3.2 m u g kg(-1), p.o. In this respect, RS 25259-197 was more potent than on dansetron and equipotent with granisetron. 4 In conscious dogs, RS 252 59-197, administered intravenously or orally, dose-dependently inhibit ed emesis induced by cisplatin (ID50 = 1.9 mu g kg(-1), i.v. and 8.5 m u g kg(-1), p.o.), dacarbazine (ID50 = 4.1 mu g kg(-1), i.v, and 9.7 m u 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 e qui-effective intravenous doses against cisplatin-induced emesis in do gs, RS 25259-197 had a longer duration of anti-emetic activity (7 h) t han 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 a pomorphine-induced emesis. 5 At doses up to 1000 mu g kg(-1), i.v., RS 25259-197 produced no meaningful haemodynamic changes in anaesthetize d dogs. 6 In summary, RS 25259-197 is a novel, highly potent and orall y active 5-HT3 receptor antagonist in vivo. With respect to its anti-e metic activity, RS 25259-197 appears to be a significant improvement o ver ondansetron in terms of potency and duration of action.