Characterization of a novel nonpeptide vasopressin V2-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes

1 We discovered the first nonpeptide arginine-vasopressin (AVP) V-2-receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V-2, V-1a and V-1b) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V-2-receptor agonist. 2 OPC-51803 and dDAVP displaced [H-3]-AVP binding to human V-2- and V-1a-receptors with K-i values of 91.9 +/- 10.8 nM (n = 6) and 3.12 +/- 0.38 nM (n = 6) for V-2-receptors, and 819 +/- 39 nM (n = 6) and 41.5 +/- 9.9 nM (n = 6) for V-1a-receptors, indicating that OPC-51803 was about nine times more selective for V-2-receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [H-3]-AVP binding to human V-1b-rcceptors even at 10(-4) M, while dDAVP showed potent affinity to human V-1b-receptors with the K-i value of 13.7 +/- 3.2 nM (n = 4). 3 OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V-2-receptors with an EC50 value of 189 +/- 14 nM (n = 6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V-2-antagonist, OPC-31260. 4 At 10(-5) M. OPC-51803 did not increase the intracellular Ca2+ concentration ([Ca2+](i)) in HeLa cells expressing human V-1a-receptors. On the other hand, dDAVP increased [Ca2+](i) in HeLa cells expressing human V-1a- and V-1b-receptors in a concentration-dependent fashion. 5 From these results, OPC-51803 has been confirmed to be the first nonpeptide agonist for human AVP V-2-receptors without agonistic activities for V-1a- and V-1b-receptors. OPC-51803 may be useful for the treatment of AVP-deficient pathophysiological states and as a tool for AVP researches.