Pharmacological profile of VP-343, a novel selective vasopressin V-2 receptor antagonist, in rats

The pharmacological profile of a novel selective vasopressin V-2 receptor a ntagonist, 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-carboxami de) was characterized in several in vitro and in vivo rat models. The IC50 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 ID50 value of 0.57 mg/kg (i.v.). VP-343 induced strong aquaresis in norm al saline-loaded conscious rats. Antidiuretic activities of VP-343 have not been detected in AVP deficient Brattleboro 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 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-333 is a potent, orally active, selective V-2 receptor antagonist, suggesting that it can be expected to be useful as an aquaretic drug.