Rm. Eglen et al., PHARMACOLOGICAL CHARACTERIZATION OF RS-25259-197, A NOVEL AND SELECTIVE 5-HT3 RECEPTOR ANTAGONIST, IN-VIVO, British Journal of Pharmacology, 114(4), 1995, pp. 860-866
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.