Effects of YM471, a nonpeptide AVP V 1A and V 2 receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells

YM471, ( Z )‐4′‐{4,4‐difluoro‐5‐[2‐(4‐dimethylaminopiperidino)‐2‐oxoethylidene]‐2,3,4,5‐tetrahydro‐1 H ‐1‐benzoazepine‐1‐carbonyl}‐2‐phenylbenzanilide monohydrochloride, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned human AVP receptors (V 1A , V 1B and V 2 ) stably expressed in Chinese hamster ovary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cells (USMC) were studied. YM471 potently inhibited specific [ 3 H]‐AVP binding to V 1A and V 2 receptors with K i values of 0.62 n M and 1.19 n M , respectively. In contrast, YM471 exhibited much lower affinity for V 1B and oxytocin receptors with K i values of 16.4 μ M and 31.6 n M , respectively. In CHO cells expressing V 1A receptors, YM471 potently inhibited AVP‐induced intracellular Ca 2+ concentration ([Ca 2+ ] i ) increase, exhibiting an IC 50 value of 0.56 n M . However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin‐induced [Ca 2+ ] i increase (IC 50 =193 n M ), and did not affect AVP‐induced [Ca 2+ ] i increase in CHO cells expressing V 1B receptors. Furthermore, in CHO cells expressing V 2 receptors, YM471 potently inhibited the production of cyclic AMP stimulated by AVP with an IC 50 value of 1.88 n M . In all assays, YM471 showed no agonistic activity. These results demonstrate that YM471 is a potent, nonpeptide human V 1A and V 2 receptor antagonist which will be a valuable tool in defining the physiologic and pharmacologic actions of AVP.British Journal of Pharmacology (2001) 133 , 746–754; doi: 10.1038/sj.bjp.0704117