title: Pharmacological characterization of RS 25259-197, a novel and selective 5-HT3 receptor antagonist, in vivo.
abstract: 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 micrograms kg-1, i.v., 3.2 micrograms kg-1, i.d. and 32.8 micrograms 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 micrograms kg-1, i.v. and 3.2 micrograms 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 micrograms kg-1, i.v. and 8.5 micrograms kg-1, p.o.), dacarbazine (ID50 = 4.1 micrograms kg-1, i.v. and 9.7 micrograms kg-1, p.o.), actinomycin D (ID50 = 4.9 micrograms kg-1, i.v. and 2.5 micrograms kg-1, p.o.) and mechlorethamine (ID50 = 4.4 micrograms kg-1, i.v. and 3.0 micrograms 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 microg kg-1, p.o., neither RS25259-197 nor ondansetron was capable of inhibiting apomorphine-induced emesis.5. At doses up to 1000 microg 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.
authors.affiliation: Institute of Pharmacology, Palo Alto, CA 94304, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: W L
authors.initials: WL
authors.lastname: Smith
authors.forename: L G
authors.initials: LG
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Clark
authors.forename: R L
authors.initials: RL
authors.lastname: Whiting
authors.forename: S S
authors.initials: SS
authors.lastname: Hegde
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005289:Ferrets; D017829:Granisetron / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D017294:Ondansetron / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077924:Palonosetron; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D012701:Serotonin / Q000031:analogs & derivatives / Q000633:toxicity; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D017829:Granisetron; D007546:Isoquinolines; D017294:Ondansetron; D000077924:Palonosetron; D011812:Quinuclidines; D012701:Serotonin; D012702:Serotonin Antagonists; C045918:2-methyl-5-HT