title: Characterization of a novel non-peptide vasopressin V1 receptor antagonist (OPC-21268) in the rat.
abstract: A non-peptide, orally effective, vasopressin (AVP) V1 receptor antagonist 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 antagonist radioligand, 125I-labelled [d(CH2)5,sarcosine7]AVP to V1 receptors in both rat liver and kidney medulla membranes. The concentration of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 40 +/- 3 nmol/l for liver V1 and 15 +/- 2 nmol/l for kidney V1 receptors (mean +/- S.E.M.; n = 3). OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)]d(CH2)5,D-Ile2,Ile4] AVP binding to V2 receptors in renal medulla membranes (IC50 > 0.1 mmol/l). After oral administration to rats, OPC-21268 was an effective V1 antagonist in a time- and dose-dependent manner. Binding kinetic studies 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 competitive effects at the renal V1 receptor. OPC-21268 shows promise as an orally active V1 antagonist.
authors.affiliation: Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Burrell
authors.forename: P A
authors.initials: PA
authors.lastname: Phillips
authors.forename: J
authors.initials: J
authors.lastname: Stephenson
authors.forename: J
authors.initials: J
authors.lastname: Risvanis
authors.forename: A M
authors.initials: AM
authors.lastname: Hutchins
authors.forename: C I
authors.initials: CI
authors.lastname: Johnston
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011485:Protein Binding; D015363:Quinolones / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D001127:Arginine Vasopressin; C068644:OPC 21268