RS-42358-197, A NOVEL AND POTENT 5-HT3 RECEPTOR ANTAGONIST, IN-VITRO AND IN-VIVO

The pharmacological activity of RS 42358-197, a novel 5-HT3 receptor a ntagonist has been evaluated in vitro and in vivo. In functional exper iments in vitro, RS 42358-197 behaved as a competitive antagonist agai nst 5-HT-induced contractions in the guinea pig ileum (low-potency pha se), yielding a pA2 estimate of 8.1. RS 42358-197 was devoid of any ag onistic or antagonistic activity at 5-HT1-like receptors (contraction of canine saphenous vein), 5-HT2 receptors (contraction of rabbit aort a) or 5-HT4 receptors (contraction of guinea pig ileum, high-potency p hase). RS 42358-197 failed to affect the concentration-effect curve to substance P in guinea pig ileum. In anesthetized rats, RS 42358-197, administered by the intravenous, intraduodenal or transdermal route, d ose-dependently inhibited the Bezold-Jarisch reflex induced by 2-methy l 5-HT (ID50:0.05 mug/kg; i.v., 5.7 mug/kg; i.d., and 11.6 mug/chamber , respectively). In this regard, when administered intraduodenally, RS 42358-197 was more potent and exhibited a longer duration of action t han either ondansetron or granisetron. In dogs, RS 42358-197, administ ered either intravenously or orally, dose-dependently inhibited the em esis induced by cisplatin, actinomycin and cyclophosphamide, but not t hat induced by apomorphine. When tested at maximally effective doses a gainst cisplatin-induced emesis in dogs, RS 42358-197 had a longer dur ation of antiemetic activity (>6 h) than ondansetron (2 h). RS 42358-1 97, administered orally, also afforded protection against cisplatin-in duced emesis in ferrets. At doses that showed marked anti-emetic activ ity in dogs (1 0-1 00 mug/kg; i.v. and 100-1000 mug/kg; i.d), RS 42358 -197 did not produce any hemodynamic changes. In conscious rats, RS 42 358-197 was found to possess gastroprokinetic activity and, in this re spect, was more potent and efficacious than ondansetron or granisetron . In summary, RS 42358-197 is a novel, potent, selective and orally ac tive 5-HT3 receptor antagonist. It may be a significant improvement ov er some of the existing 5-HT3 receptor antagonists, such as ondansetro n and granisetron, in terms of potency and duration of action.