Characterization of a novel aquaretic agent, OPC‐31260, as an orally effective, nonpeptide vasopressin V₂ receptor antagonist

Abstract

1 OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2 OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 + 0.2 x 106M and 1.4 + 0.2 x 10-8M, respectively. 3 OPC-31260 at doses of 10 to 100pg kg-', i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4 After oral administration at doses of 1 to 30mgkg-1 in normal conscious rats, OPC-31260 dosedependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5 The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention.

Hyponatremia in cirrhosis: From pathogenesis to treatment

“…119 The feasibility of the second option (i.e., to block the V 2 receptor) has been demonstrated by several compounds that promote aquaresis in experimental animals. [120][121][122][123] The third therapeutical strategy is represented by demeclocycline, which was the first inhibitor of the renal effect of VP used in humans. This tetracycline acts by interfering with the generation and action of cAMP in the cortical and medullary collecting ducts.…”

Wortmannin inhibits the activation of MAP kinase following vasopressin V1 receptor stimulation

“…2A). The ICs~ of OPC-21268 for the displacement of specific AVP binding is reported to be 4x 10 -~ M and >10 -~ M for VI and V2 receptors, respectively [18], and the 1C~, of OPC-31260 for the displacement of specific AVP binding is reported to be 1.2 x 10 ~' M and 1.4 x 10 s M for VI and V2 receptors, respectively [19]. Thus.…”

Blocking Effects of OPC-21268 and OPC-31260 (Vasopressin V1- and V2-Receptor Antagonists) on Vasopressin-Induced Constrictions in Isolated, Perfused Dog Femoral Arteries

“…In experiments in vivo, it acted as a specific antagonist of the VP-induced pressor re sponse in pithed rats and conscious rats (4). More re cently, it was reported that OPC-31260 selectively antagonized binding to the V2-subtype of the VP recep tor in a competetive manner (5).…”

“…Recently, nonpeptide V1 and V2-receptor antago nists were developed, i.e., OPC-21268 and OPC-31260, respectively (4,5). OPC-21268 selectively antagonized binding to the V1-subtype of the VP-receptor in a com petitive manner (4).…”