EFFECTS OF AN ORALLY ACTIVE VASOPRESSIN V(1)-RECEPTOR ANTAGONIST

1. This paper reports on the in vitro and in vivo characteristics of a non-peptide vasopressin V1 receptor antagonist 1-{1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinolinone (OPC-21268). 2. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor antagonist radioligand, [I-125]-[d(CH2)5, sarcosine7]AVP from vasopressin V1 receptors in rat liver and kidney membranes, inhibitory concentration of 50% (IC50) 4 x 10(-8), 0.3 mol/L liver and 1.5 x 10(-8), 0.2 mol/L kidney. OPC-21268 had little effect on the seleCtive V2 antagonist radioligand [H-3]desGly-NH29-d(CH2)5[D-Ileu2, Ileu4]AVP binding to V2 receptors in renal membranes (IC50 > 10(-4) mol/L). 3. After oral administration to rats, OPC-21268 was an effective V1 antagonist to both liver and kidney V1 receptors, in a dose-dependent manner. 4. These studies confirm that OPC-21268 is a potent non-peptide, orally effective V1 vasopressin receptor antagonist.