Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist

摘要

A possible role of arginine vasopressin (AVP) V1b receptor subtype in stress-related disorders has been recently highlighted by the discovery of the agonist [1-deamino-4-cyclohexylalanine] AVP (d[Cha4]AVP) and the antagonist SSR149415. Both compounds have been proposed to target specifically V1b receptors, since the reported affinities for the related V1a, V2 and oxytocin receptors are in the micromolar or submicromolar range. In the present study, we further investigated the binding affinities of d[Cha4]AVP and SSR149415 at recombinant human vasopressin V1b (hV1b) and oxytocin (hOT) receptors expressed in Chinese hamster ovary (CHO) cells and functional properties of both compounds at hV1b, hV1a, hV2 and hOT receptors.d[Cha4]AVP bound to hV1b receptors and hOT receptors with pKi values of 9.68±0.06 and 7.68±0.09, respectively. SSR149415 showed pKi values of 9.34±0.06 at hV1b and 8.82±0.16 at hOT receptors.d[Cha4]AVP stimulated [Ca2+]i increase in hV1b-CHO cells with a pEC50 value of 10.05±0.15. It showed pEC50 values of 6.53±0.17 and 5.92±0.02 at hV1a and hV2 receptors, respectively, and behaved as a weak antagonist at hOT receptors (pKB=6.31±0.12). SSR149415 inhibited the agonist-induced [Ca2+]i increase with pKB values of 9.19±0.07 in hV1b-CHO and 8.72±0.15 in hOT-CHO cells. A functional pKi value of 7.23±0.10 was found for SSR1494151 at hV1a receptors, whereas it did not inhibit 20 nM AVP response at hV2 receptors up to 3 μM.Data obtained confirmed the high potency and selectivity of d[Cha4]AVP at hV1b receptors, but revealed that SSR149415, in addition to the high potency at hV1b receptors, displays a significant antagonism at hOT receptors.