Vasopressin and a nonpeptide antidiuretic hormone receptor antagonist (OPC-31260)

The development of nonpeptide orally active AVP analogues has provided a new tool with which to assess the physiological and pathophysiological role of vasopressin (AVP). We have previously characterised the nonpeptide vasopressin V1 receptor antagonist OPC-21268, and now report the in vitro characterisation of the nonpeptide V2 receptor antagonist OPC-31260 in the rat. OPC-31260 caused a concentration-dependent displacement of the selective AVP V2 receptor antagonist radioligand, [³H]desGly-NH₂⁹[d(CH₂)₅, D-Ile², Ile⁴] AVP from V2 receptors in rat kidney medulla membranes. The concentration of OPC-31260 that displaced 50% of specific AVP binding (IC₅₀) was 20 ± 2 nmol/l for renal V2 receptors. OPC-31260 also caused a concentration-dependent displacement of the selective AVP V1 receptor antagonist radioligand, [¹²⁵I]-[d(CH₂)₅, sarcosine⁷] AVP from V1 receptors in both rat liver and kidney medulla membranes. The IC₅₀ was 500 ± 30 nmol/ 1 for both renal and liver V1 receptors. After oral administration to rats, OPC-31260 was an effective inhibitor of AVP at renal V2 and liver V1 receptors in a time-dependent manner. In vitro binding kinetic studies showed that OPC-31260 was a competitive antagonist at both the renal V2 receptor and the hepatic V1 receptor. OPC-31260 is a nonpeptide, orally effective competitive inhibitor of AVP with a V2: V1 receptor selectivity ratio of 25:1 indicating relative V2 receptor selectivity.