Antidiuretic Effects of a Novel Nonpeptide Vasopressin V₂-Receptor Agonist, OPC-51803, Administered Orally to Dogs

Abstract

We elucidated the pharmacological properties of a novel nonpeptide vasopressin V₂-receptor agonist, OPC-51803 ((5R)-2-[1-(2-chloro-4-(1-pyrrolidinyl)benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]-N-isopropylacetamide), via both in vitro binding experiments incorporating canine kidney and platelet membrane fractions and in vivo experiments that would determine the compound’s antidiuretic effects after oral administration to water-loaded dogs. OPC-51803 displaced [³H]arginine vasopressin (AVP) binding to canine V₂ and V_1a receptors, as determined by resulting K_i values of 15.2 ± 0.6 nM (n = 4) and 653 ± 146 nM (n = 4), respectively. These data indicate that OPC-51803 was about 43 times more selective for V₂ receptors than for V_1a receptors. Antidiuretic studies showed that orally administered doses of OPC-51803 (0.03 to 0.3 mg · kg⁻¹) decreased urine volume and increased urinary osmolality in a dose-dependent manner in water-loaded dogs. Intravenous OPC-51803 infusions (0.3 and 3 μg · kg⁻¹ · min⁻¹) did not affect renal or systemic hemodynamics in anesthetized dogs. Since these results confirm that OPC-51803 shows antidiuretic action in dogs, the compound may be useful for treating AVP-deficient pathophysiological states.