title: Development of potent serotonin-3 (5-HT3) receptor antagonists. I. Structure-activity relationships of 2-alkoxy-4-amino-5-chlorobenzamide derivatives.
abstract: A new series of 2-alkoxy-4-amino-5-chlorobenzamide derivatives bearing five- to seven-membered heteroalicyclic rings in the amine moiety was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity by assaying the ability to antagonize the von Bezold-Jarisch reflex in rats. The five- to seven-membered heteroalicycles comprise pyrrolidine, morpholine, 1,4-thiazine, piperidine, piperazine, 1,4-oxazepine, 1,4-thiazepine, azepine, and 1,4-diazepine rings. Among them, some benzamide derivatives having a 1,4-diazepine ring showed a potent 5-HT3 receptor antagonistic activity. In particular, 4-amino-5-chloro-N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6- yl)-2- ethoxybenzamide (96) and the 1-benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 103 showed potent 5-HT3 receptor antagonistic activity without 5-HT4 receptor binding affinity.
authors.affiliation: Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Morie
authors.forename: Y
authors.initials: Y
authors.lastname: Hirokawa
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002945:Cisplatin; D005289:Ferrets; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D002945:Cisplatin