VPA-985, a Nonpeptide Orally Active and Selective Vasopressin V2 Receptor Antagonist

Abstract

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

A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: A multicenter, randomized, placebo-controlled trial

“…In normal anesthetized rats, VPA-985 and furosemide decreased urinary osmolality to a similar extent, whereas the combination produced a slightly greater decrease in urinary osmolality. 12 Therefore, it appears that the aquaretic effect of VPA-985 is independent of the NaCl reabsorption proximal to the renal collecting tubules. This offers the potential for combination therapy in conditions of sodium retention and hyponatremia, such as liver cirrhosis with ascites.…”

“…12 It has the advantage over other vasopressin receptor antag-onists of a greater specific selectivity for the V 2 receptors in the renal collecting tubule 29 and, therefore, increased potency of action. 13 The lack of agonist action further enhances its potency.…”

“…The aquaretic effects of VPA-985 are dependent on the generation of free water in the thick ascending limb of the Loop of Henle, which, in turn, is dependent on the reabsorption of NaCl at the same site. 12 Therefore, theoretically, the inhibition of NaCl reabsorption in the thick ascending limb of the Loop of Henle such as the concomitant administration of furosemide should reduce the efficacy of VPA-985. In normal anesthetized rats, VPA-985 and furosemide decreased urinary osmolality to a similar extent, whereas the combination produced a slightly greater decrease in urinary osmolality.…”

“…It is a competitive inhibitor of vasopressin binding to V 2 receptors. 12 It has been shown to promote renal water excretion without affecting renal electrolyte excretion, thereby improving serum sodium concentration. 13 Therefore, the aims of this study were to assess (1) the safety and efficacy of different doses of VPA-985 in correcting hyponatremia in patients with edematous states, including liver cirrhosis with ascites and heart failure and syndrome of inappropriate antidiuretic hormone (SIADH), and (2) the effect of VPA-985 on overall patient symptomatology.…”

Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

“…Lixivaptan inhibits AVP binding to the V 1a R with an IC 50 of 230 nM and to the V 2 R with an IC 50 of 1.2±0.1 nM [53]. Furthermore, lixivaptan has higher affinity for the V 2 R than other AVP receptor antagonists, as demonstrated in human and rat studies [53,54]. Lixivaptan is currently undergoing Phase III clinical trials to determine its possible role in the treatment of hyponatremia assosciated with CHF, cirrhosis and SIADH.…”