Pharmacological Profile of VP-343,a Novel Selective Vasopressin V_2 Receptor Antagonist, in Rats

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The pharamacological profile of a novel selective vasopressin V_2 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 IC_<50> values of VP-343 for vasopressin V_<1A> and V_2 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 ID_<50> 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 Bratteleboro rats, showing its lack AVP V_2 agonistic activity. During repeated administration for 21 d (3 mg/kg, p.o.) and after recovery, the aquaretic action 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 V_2 receptor antagonist, suggesting that it can be expected to be useful as an aquaretic drug.
公益社団法人日本薬学会の論文
2000-02-01