CHARACTERIZATION OF A NOVEL NONPEPTIDE VASOPRESSIN V(1) RECEPTOR ANTAGONIST (OPC-21268) IN THE RAT

A non-peptide, orally effective, vasopressin (AVP) V1 receptor antagon ist 1-{1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl} -3,4-dihydro- 2(1H)-quinolinone (OPC-21268) has recently been described. This paper reports the in-vitro and in-vivo characterization of OPC-21268 binding to vasopressin receptors in rat liver and kidney. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor anta gonist radioligand, I-125-labelled [d(CH2)5, sarcosine7]AVP to V1 rece ptors in both rat liver and kidney medulla membranes. The concentratio n of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 4 0 +/- 3 nmol/l for liver V1 and 15 +/- 2 nmol/l for kidney V1 receptor s (mean +/- S.E.M.; n = 3). OPC-21268 had little effect on the selecti ve V2 antagonist radioligand [H-3] desGly-NH29[d(CH2)5,D-Ile2,Ile4] AV P binding to V2 receptors in renal medulla membranes (IC50 > 0.1 mmol/ l). After oral administration to rats, OPC-21268 was an effective V1 a ntagonist in a time- and dose-dependent manner. Binding kinetic studie s showed that OPC-21268 acted as a competitive antagonist at the liver V1 receptor in vitro and in vivo, in addition to its in-vitro competi tive effects at the renal V1 receptor. OPC-21268 shows promise as an o rally active V1 antagonist.