title: Pharmacological profile of VP-343, a novel selective vasopressin V2 receptor antagonist, in rats.
abstract: The pharmacological profile of a novel selective vasopressin V2 receptor antagonist, 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-carboxamide) was characterized in several in vitro and in vivo rat models. The IC50 values of VP-343 for vasopressin V1A and V2 receptors were 110 and 0.77 nM, respectively. VP-343 inhibited dose-dependently the pressor response to exogenous arginine vasopressin (AVP; 30 mU/kg, i.v.) in pithed rats, with an ID50 value of 0.57 mg/kg (i.v.). VP-343 induced strong aquaresis in normal saline-loaded conscious rats. Antidiuretic activities of VP-343 have not been detected in AVP deficient Brattleboro rats, showing its lack AVP V2 agonistic activity. During repeated administration for 21 d (3 mg/kg, p.o.) and after recovery, the aquaretic action of VP-343 still remained. In the aged (17 month) saline-loaded conscious rats study, VP-343 (3 mg/kg, p.o.) exhibited remarkable diuretic action. In a single dose oral toxicity study in mice, VP-343 did not produce any clinical signs and mortality at any of the tested doses. The results indicate that VP-343 is a potent, orally active, selective V2 receptor antagonist, suggesting that it can be expected to be useful as an aquaretic drug.
authors.affiliation: Sagami Research Laboratory, Wakamoto Pharmaceutical Co., Ltd., Ashigarakamigun, Kanagawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Naito
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtake
authors.forename: H
authors.initials: H
authors.lastname: Hasegaw
authors.forename: A Y
authors.initials: AY
authors.lastname: Fukaya
authors.forename: T
authors.initials: T
authors.lastname: Kurasawa
authors.forename: K
authors.initials: K
authors.lastname: Naito
authors.forename: H
authors.initials: H
authors.lastname: Matsukawa
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
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Koike
authors.forename: K
authors.initials: K
authors.lastname: Shigenobu
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology* / Q000633:toxicity; D004573:Electrolytes / Q000652:urine; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D011810:Quinoxalines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011910:Rats, Brattleboro; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D014563:Urodynamics / Q000187:drug effects
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D004573:Electrolytes; D011758:Pyrroles; D011810:Quinoxalines; D017483:Receptors, Vasopressin; C120959:VP 343; C106389:conivaptan; C076251:mozavaptan; D005665:Furosemide