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Vol. 300, Issue 3, 1122-1130, March 2002
Exploratory Research Department (C.S.-L.G., G.B., M.P., R.P.),
Cardiovascular-Thrombose Research (J.W., C.L., D.N.), Central Nervous
System Research Department (J.S., G.Gr., P.S.), and Discovery Research
Division (J.P.M., B.S., G.LF), Sanofi-Synthelabo Recherche, Toulouse,
Montpellier et Bagneux, France; and Institut National de la Santé
et de la Recherche Médicale, Montpellier, France (G.Gu.,
C.B.)
(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 V1b receptor antagonist yet described, has been
characterized in vitro and in vivo. SSR149415 showed competitive
nanomolar affinity for animal and human V1b receptors and
exhibited much lower affinity for rat and human V1a,
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 V1b 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 V1b receptor antagonist. It represents a unique tool
for exploring the functional role of V1b receptors and
deserves to be clinically investigated in the field of stress and anxiety.
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