Effects of YM218, a nonpeptide vasopressin V1A receptor-selective antagonist, on human vasopressin and oxytocin receptors

The binding and signal transduction characteristics of YM218 ((Z)-4′-{4,4-difluoro-5-[2-oxo-2-(4-piperidinopiperidino)ethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl}-2-methyl-3-furanilide hemifumarate), a newly synthesized, potent arginine vasopressin (AVP) V1A receptor-selective antagonist, were examined using cloned human AVP receptors (V1A, V1B and V2) stably expressed in Chinese hamster ovary (CHO) cells and human uterine smooth muscle cells (USMCs) expressing oxytocin receptors. YM218 potently inhibited specific binding of [3H] AVP to V1A receptors, exhibiting a Ki value of 0.30 nM. In contrast, YM218 exhibited much lower affinity for V1B, V2 and oxytocin receptors, exhibiting Ki values of 25,500 nM, 381 nM and 71.0 nM, respectively. In CHO cells expressing V1A receptors, YM218 potently inhibited the AVP-induced increase in intracellular Ca2+ concentration ([Ca2+]i), exhibiting an IC50 value of 0.25 nM. However, in human USMCs expressing oxytocin receptors, YM218 exhibited a much lower potency in inhibiting the oxytocin-induced [Ca2+]i increase, showing an IC50 value of 607 nM, and had no effect on the AVP-induced [Ca2+]i increase in CHO cells expressing V1B receptors. Furthermore, in CHO cells expressing V2 receptors, YM218 did not potently inhibit the production of cAMP stimulated by AVP, showing an IC50 value of 62.2 nM. In all assays used, YM218 did not exhibit any agonistic activity. These results demonstrate that YM218 is a potent, nonpeptide human V1A receptor-selective antagonist, and that YM218 will be a valuable new tool to gain further insight into the physiologic and pharmacologic actions of AVP.