title: Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.
abstract: The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.
authors.affiliation: Research Laboratory, Dainippon Pharmaceutical Company, Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Morie
authors.forename: T
authors.initials: T
authors.lastname: Kon
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: T
authors.initials: T
authors.lastname: Karasawa
authors.forename: J
authors.initials: J
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D020117:Cisapride; D004285:Dogs; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008787:Metoclopramide / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; D010880:Piperidines; D012702:Serotonin Antagonists; C062720:mosapride; D008787:Metoclopramide; D020117:Cisapride