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SR 121463A, a potent and selective, orally active, nonpep-tide vasopressin V 2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V 2 receptors in rat, bovine and human kidney (0.6 K i [nM] 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (K i 0.26 0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [ 3 H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V 2 receptors. In comparison, the nonpeptide V 2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V 2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (K i in the 10 nanomolar range). Moreover , OPC-31260 exhibited a poor V 2 selectivity profile and can be considered as a V 2 /V 1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na and K excretions unlike that of known diuretic agents such as furosemide or hydrochloro-thiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattle-boro rats. Thus, SR 121463A is the most potent and selective , orally active V 2 antagonist yet described and could be a powerful tool for exploring V 2 receptors and the therapeutical usefulness of V 2 blocker aquaretic agents in water-retaining diseases. (J. Clin. Invest. 1996. 98:2729-2738.) Key words: SR 121463A • vasopressin • nonpeptide antagonist • V 2 receptor • aquaretic

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