In vitro and in vivo pharmacological characterisation of the potent and selective vasopressin V1A receptor antagonist 4-[4-(4-Chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl-(3,5-difluoro-phenyl) methanone (PF-00738245)

Abstract The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin receptors plays an important role in disease conditions including polycystic kidney disease, congestive heart failure and dysmenorrhoea. The development of potent and selective vasopressin receptor ligands is needed to help dissect the function of the specific subtypes in disease pathogenesis. Here we report the pharmacological characterisation of PF-00738245 in in vitro binding and functional assays using cells expressing vasopressin V 1A , V 1B or V 2 receptors. PF-00738245 inhibited AVP binding to the recombinant human vasopressin V 1A receptor (K i  = 2.85 nM) and blocked AVP-induced rat aortic ring and human myometrial contraction (pK B  = 7.35 and 8.62 respectively). PF-00738245 was selective for the vasopressin V 1A receptor by demonstrating minimal binding to vasopressin V 1B (3.6% inhibition at 10 μM) or functional activity at vasopressin V 2 receptors (8.1% agonist and − 8.4% antagonist activity at 10 μM) as well as the oxytocin receptor (46.3% antagonist activity at 10 μM). The in vivo pharmacological properties were tested orally in the rat and PF-00738245 dose dependently blocked the effect of AVP on a capsaicin-induced cutaneous flare response. Taken together the data support the use of PF-00738245 as a potent and selective vasopressin V 1A receptor antagonist which may have utility in the treatment of disease conditions which are propagated by elevation in vasopressin V 1A receptor signalling.