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

• Published in: Journal of Pharmacological Sciences Vol. 94; no. 4; pp. 426 - 433
• Main Authors: Nakamura, Shigeki, Hirano, Takahiro, Onogawa, Toshiyuki, Itoh, Shuji, Hashimoto, Ayako, Yamamura, Yoshitaka, Kondo, Kazumi, Mori, Toyoki, Kambe, Toshimi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 2004; The Japanese Pharmacological Society; Elsevier
• Subjects: antidiuresis; nonpeptide; OPC-51803; V2 agonist; antidiuresis; nonpeptide; OPC-51803; V2 agonist
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.94.426

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-tetra-hydro-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 V1a receptors, as determined by resulting Ki 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 V1a 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.