title: Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.
abstract: A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawakita
authors.forename: T
authors.initials: T
authors.lastname: Kuroita
authors.forename: M
authors.initials: M
authors.lastname: Yasumoto
authors.forename: M
authors.initials: M
authors.lastname: Sano
authors.forename: K
authors.initials: K
authors.lastname: Inaba
authors.forename: T
authors.initials: T
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Tahara
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002945:Cisplatin / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011814:Quipazine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000932:Antiemetics; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010078:Oxazines; D012702:Serotonin Antagonists; D011814:Quipazine; D013134:Spiperone; C070671:azasetron; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin