title: Pharmacological effects of the new gastroprokinetic agent mosapride citrate and its metabolites in experimental animals.
abstract: The pharmacological effects of the metabolites M1 and M2 of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholi nyl] methyl]benzamide citrate, AS-4370, CAS 112885-42-4), a gastroprokinetic agent with serotonin 5-HT4 receptor agonist property, were compared with those of mosapride. In isolated guinea-pig ileum treated with phenoxybenzamine, the metabolites M1 and M2 enhanced electrically-evoked contractions with EC50 values of 1.2 x 10(-7) mol/l and 1.0 x 10(-6) mol/l, respectively. The metabolite M1 was twice less potent than that of mosapride. When administered intravenously, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats; the potency was 3 times less than that of mosapride in mice and almost equal to that of mosapride in rats. When administered orally, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats, and also enhanced gastric emptying of a resin pellet meal in rats. The potency of metabolite M1 was 10 times less than that of mosapride in rats, although it was equal to that of mosapride in mice. In these experiments, the metabolite M2 was far less active. In addition to these gastroprokinetic properties, the metabolite M1 possessed a potent 5-HT3 receptor antagonist property. The metabolite M1 antagonized the 2-methyl-5-HT-induced bradycardia in anesthetized rats with an ED50 value of 10.5 micrograms/kg, i.v., and inhibited the cisplatin-induced emesis in ferrets with a potency approximately 25 times that of mosapride. These results suggest that the metabolites M1 and M2 of mosapride do not play a crucial role in the gastroprokinetic effect of mosapride.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: H
authors.initials: H
authors.lastname: Omoya
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D004639:Emetics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D005289:Ferrets; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D004639:Emetics; D005765:Gastrointestinal Agents; D009025:Morpholines; D017366:Serotonin Receptor Agonists; C062720:mosapride; D002945:Cisplatin