title: Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives.
abstract: The intent of the work was to study the structure-activity relationships of AVP receptor antagonists bearing a chiral ring as a partial structure since such studies had been reported for only achiral compounds. In the present paper, we deal with compounds consisting of the chiral tricyclic hetero ring (1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and 1,2,3,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine) and 2-phenylbenzanilide analogues. These compounds exhibited a highly selective affinity for V2 receptor, and their stereochemical configuration had a great influence on V2 receptor binding. VP-343 (N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a] quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl]-2-ca rboxamide), VP-365 (N-[4-[[(11aS)-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benz odiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl-2-carboxamide) and VP-339 (N-[4-[[(11aS)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]+ ++benzodiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl]-2-carboxami de) were the most potent compounds in vitro and in vivo. The IC50 values of VP-343, VP-365 and VP-339 against V2 receptor were 0.772, 1.18 and 0.216 nM, respectively. The ED300 values (dose required to increase three times the urine volume of the control rats; oral administration) of VP-343, VP-365 and VP-339 were 0.22, 0.31 and 0.78 mg/kg, respectively.
authors.affiliation: Sagami Research Laboratories, Wakamoto Pharmaceutical Co., Ltd., Ashigarakami-gun, Kanagawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtake
authors.forename: A
authors.initials: A
authors.lastname: Naito
authors.forename: H
authors.initials: H
authors.lastname: Hasegawa
authors.forename: K
authors.initials: K
authors.lastname: Kawano
authors.forename: D
authors.initials: D
authors.lastname: Morizono
authors.forename: M
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Matsukawa
authors.forename: K
authors.initials: K
authors.lastname: Naito
authors.forename: T
authors.initials: T
authors.lastname: Oguma
authors.forename: Y
authors.initials: Y
authors.lastname: Ezure
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuriya
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014667:Vasopressins / Q000187:drug effects / Q000378:metabolism
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D004232:Diuretics; D011758:Pyrroles; D011810:Quinoxalines; C120957:VP 339; C120959:VP 343; C120958:VP 365; D014667:Vasopressins; D001569:Benzodiazepines