Characterization of (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), a selective and orally active vasopressin V1b receptor antagonist.
(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.
Serradeil-Le Gal
Claudine
C
Exploratory Research Department, Sanofi-Synthelabo Recherche, Toulouse, Montpellier et Bagneux, France. claudine.serradeil@sanofi-synthelabo.com
Wagnon
Jean
J
Simiand
Jacques
J
Griebel
Guy
G
Lacour
Colette
C
Guillon
Gilles
G
Barberis
Claude
C
Brossard
Gabrielle
G
Soubrié
Philippe
P
Nisato
Dino
D
Pascal
Marc
M
Pruss
Rebecca
R
Scatton
Bernard
B
Maffrand
Jean-Pierre
JP
Le Fur
Gérard
G
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000494:pharmacology; D016466:CHO Cells; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003681:Dehydration / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism
D014151:Anti-Anxiety Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D009025:Morpholines; D013141:Spiro Compounds; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; C103281:satavaptan