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

1 YM471, (Z)-4'-{4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylid ene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl}-2-phenylbenzanilide m onohydrochloride, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned hum an AVP receptors (V-1A, V-1B and V-2) stably expressed in Chinese hamster o vary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cel ls (USMC) were studied. 2 YM471 potently inhibited specific [H-3]-AVP binding to V-1A and V-2 recep tors with K-i values of 0.62 nhl and 1.19 nM, respectively. In contrast, YM 471 exhibited much lower affinity for V-1B and oxytocin receptors with K-i values of 16.4 muM and 31.6 nM, respectively. 3 In CHO cells expressing V-1A receptors, YM471 potently inhibited AVP-indu ced intracellular Ca2+ concentration ([Ca2+](i)) increase, exhibiting an IC 50 value of 0.56 nM. However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin-induced [Ca2+](i) increase (IC50 = 193 nM), and did not affect AVP-induced [Ca2+](i) increas e in CI-IO cells expressing VIE receptors. Furthermore, in CHO cells expres sing Vt receptors, YM471 potently inhibited the production of cyclic AMP st imulated by AVP with an IC50 value of 1.88 nhl. In all assays, YM471 showed no agonistic activity. 4 These results demonstrate that YM471 is a potent, nonpeptide human VIA an d Vt receptor antagonist which will be a valuable tool in defining the phys iologic and pharmacologic actions of AVP.