title: Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists.
abstract: The present study was undertaken to evaluate whether a novel series of 2,6-diaza-5-oxobicyclo[5.4.0]undeca-1(7),8,10-triene derivatives exhibited antagonistic activity for vasopressin V1 and V2 receptors. Most of these compounds were synthesized and showed a high affinity potential for V2 receptor and low to moderate affinity potential for V1 receptor. The most potent and V2-selective compound, N-[4-[2,6-diaza-6-[2-(4-methylpiperazinyl)-2-oxoethyl] -5- oxobicyclo[5.4.0]undeca-1(7),8,10-trien-2-yl]-carbonyl]pheny l][2-(4- methylphenyl)phenyl]-formamide (11b), exhibited IC50's of 2.9 nM for the V2 receptor and 200 nM for the V1 receptor, respectively. When administered orally to rat, 11b showed an approximately 18-fold increased urine volume in comparison with control rat.
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001570:Benzodiazepinones / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D013329:Structure-Activity Relationship