Characterization of a novel nonpeptide vasopressin V 2 ‐agonist, OPC‐51803, in cells transfected human vasopressin receptor subtypes

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. OPC‐51803 and dDAVP displaced [ 3 H]‐AVP binding to human V 2 ‐ and V 1a ‐receptors with K i values of 91.9±10.8 n M ( n =6) and 3.12±0.38 n M ( n =6) for V 2 ‐receptors, and 819±39 n M ( n =6) and 41.5±9.9 n M ( 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 [ 3 H]‐AVP binding to human V 1b ‐receptors 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 n M ( n =4). OPC‐51803 concentration‐dependently increased cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) production in HeLa cells expressing human V 2 ‐receptors with an EC 50 value of 189±14 n M ( 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. At 10 −5   M , OPC‐51803 did not increase the intracellular Ca 2+ concentration ([Ca 2+ ] i ) in HeLa cells expressing human V 1a ‐receptors. On the other hand, dDAVP increased [Ca 2+ ] i in HeLa cells expressing human V 1a ‐ and V 1b ‐receptors in a concentration‐dependent fashion. 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.British Journal of Pharmacology (2000) 129 , 1700–1706; doi: 10.1038/sj.bjp.0703221