Pharmacological characterization of RS 25259‐197, a novel and selective 5‐HT3 receptor antagonist, in vivo

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Abstract
The pharmacological effects in vivo, of RS 25259‐197, a selective 5‐HT3 receptor antagonist, have been investigated. 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 μg kg−1, i.v., 3.2 μg kg−1, i.d. and 32.8 μg 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. 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 μg kg−1, i.v. and 3.2 μg kg−1, p.o. In this respect, RS 25259‐197 was more potent than ondansetron and equipotent with granisetron. In conscious dogs, RS 25259‐197, administered intravenously or orally, dose‐dependently inhibited emesis induced by cisplatin (ID50 = 1.9 μg kg−1, i.v. and 8.5 μg kg−1, p.o.), dacarbazine (ID50 = 4.1 μg kg−1, i.v. and 9.7 μg kg−1, p.o.), actinomycin D (ID50 = 4.9 μg kg−1, i.v. and 2.5 μg kg−1, p.o.) and mechlorethamine (ID50 = 4.4 μg kg−1, i.v. and 3.0 μg 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 μg kg−1, p.o., neither RS 25259‐197 nor ondansetron was capable of inhibiting apomorphine‐induced emesis. At doses up to 1000 μg kg−1, i.v., RS 25259‐197 produced no meaningful haemodynamic changes in anaesthetized dogs. 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.