CHARACTERIZATION OF SR 121463A, A HIGHLY POTENT AND SELECTIVE, ORALLY-ACTIVE VASOPRESSIN V-2 RECEPTOR ANTAGONIST

SR 121463A, a potent and selective, orally active, nonpeptide vasopres sin V-2 receptor antagonist, has been characterized in several in vitr o and in vivo models. This compound displayed highly competitive and s elective affinity for V-2 receptors in rat, bovine and human kidney (0 .6 less than or equal to K-i [nM] less than or equal to 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopress in (AVP)-stimulated adenylyl cyclase activity (K-i = 0.26+/-0.04 nM) w ithout any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [H-3]AVP label ing especially in the medullo-papillary region and confirmed that it i s a suitable tool for mapping V-2 receptors. In comparison, the nonpep tide V-2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V-2 receptors and lower efficacy to inhibit vasopressi n-stimulated adenylyl cyclase (K-i in the 10 nanomolar range). Moreove r, OPC-31260 exhibited a poor V-2 selectivity profile and can be consi dered as a V-2/V-1a ligand. In normally hydrated conscious rats, SR 12 1463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) o r oral (0.03-10 mg/kg) administration. The effect was dose-dependent a nd lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a si milar aquaretic profile but with markedly lower oral efficacy, The act ion of SR 121463A was purely aquaretic with no changes in urine Na+ an d K+ excretions unlike that of known diuretic agents such as furosemid e or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro ra ts, 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 aquaret ic agents in water-retaining diseases.