BIOCHEMICAL AND PHARMACOLOGICAL PROPERTIES OF SR-49059, A NEW, POTENT, NONPEPTIDE ANTAGONIST OF RAT AND HUMAN VASOPRESSIN V1A RECEPTORS

SR 49059, a new potent and selective orally active, nonpeptide vasopre ssin (AVP) antagonist has been characterized in several in vitro and i n vivo models. SR 49059 showed high affinity for V1a receptors from ra t liver (K(i) = 1.6 +/- 0.2) and human platelets, adrenals, and myomet rium (K(i) ranging from 1.1 to 6.3 nM). The previously described nonpe ptide V1 antagonist, OPC-21268, was almost inactive in human tissues a t concentrations up to 100 muM. SR 49059 exhibited much lower affinity (two orders of magnitude or more) for AVP V2 (bovine and human), V1b (human), and oxytocin (rat and human) receptors and had no measurable affinity for a great number of other receptors. In vitro, AVP-induced contraction of rat caudal artery was competitively antagonized by SR 4 9059 (pA2 = 9.42). Furthermore, SR 49059 inhibited AVP-induced human p latelet aggregation with an IC50 value of 3.7 +/- 0.4 nM, while OPC-21 268 was inactive up to 20 muM. In vivo, SR 49059 inhibited the pressor response to exogenous AVP in pithed rats (intravenous) and in conscio us normotensive rats (intravenous and per os) with a long duration of action (> 8 h at 10 mg/kg p.o). In all the biological assays used, SR 49059 was devoid of any intrinsic agonistic activity. Thus, SR 49059 i s the most potent and selective nonpeptide AVP V1a antagonist describe d so far, with marked affinity, selectivity, and efficacy toward both animal and human receptors. With this original profile, SR 49059 const itutes a powerful tool for exploring the therapeutical usefulness of a selective V1a antagonist.