Abstract

(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), the first selective, nonpeptide vasopressin V_1b receptor antagonist yet described, has been characterized in vitro and in vivo. SSR149415 showed competitive nanomolar affinity for animal and human V_1b receptors and exhibited much lower affinity for rat and human V_1a, V₂, and oxytocin receptors. Moreover, this compound did not interact with a large number of other receptors, enzymes, or ion channels. In vitro, SSR149415 behaved as a full antagonist and potently inhibited arginine vasopressin (AVP)-induced Ca²⁺ increase in Chinese hamster ovary cells expressing rat or human V_1b receptors. The in vivo activity of SSR149415 has been studied in several models of elevated corticotropin secretion in conscious rats. SSR149415 inhibited exogenous AVP-induced increase in plasma corticotropin, from 3 mg/kg i.p. and 10 mg/kg p.o. upwards. Similarly, this compound antagonized AVP-potentiated corticotropin release provoked by exogenous corticoliberin at 3 mg/kg p.o. The effect lasted for more than 4 h at 10 mg/kg p.o. showing a long-lasting oral effect. SSR149415 (10 mg/kg p.o.) also blocked corticotropin secretion induced by endogenous AVP increase subsequent to body water loss. Moreover, 10 mg/kg i.p SSR149415 inhibited plasma corticotropin elevation after restraint-stress in rats by 50%. In the four-plate test, a mouse model of anxiety, SSR149415 (3 mg/kg p.o. upwards) displayed anxiolytic-like activity after acute and 7-day repeated administrations. Thus, SSR149415 is a potent, selective, and orally active V_1b receptor antagonist. It represents a unique tool for exploring the functional role of V_1b receptors and deserves to be clinically investigated in the field of stress and anxiety.