TY - JOUR T1 - SSR126768A (4-Chloro-3-[(3<em>R</em>)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2- oxo-2,3-dihydro-1<em>H</em>-indol-3-yl]-<em>N</em>-ethyl-<em>N</em>-(3-pyridylmethyl)-benzamide, Hydrochloride): A New Selective and Orally Active Oxytocin Receptor Antagonist for the Prevention of Preterm Labor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 414 LP - 424 DO - 10.1124/jpet.103.061200 VL - 309 IS - 1 AU - Claudine Serradeil-Le Gal AU - Gérard Valette AU - Loïc Foulon AU - Guy Germain AU - Charles Advenier AU - Emmanuel Naline AU - Marc Bardou AU - Jean-Pierre Martinolle AU - Brigitte Pouzet AU - Danielle Raufaste AU - Corinne Garcia AU - Eléonore Double-Cazanave AU - Maxime Pauly AU - Marc Pascal AU - Alain Barbier AU - Bernard Scatton AU - Jean-Pierre Maffrand AU - Gérard Le Fur Y1 - 2004/04/01 UR - http://jpet.aspetjournals.org/content/309/1/414.abstract N2 - 4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (Ki = 0.44 nM) and exhibited much lower affinity for V1a, V1b, and V2 receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 μM). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I125]d(CH2)5[Tyr(Me)2, Thr4, Orn8125I-Tyr-NH29]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca2+ increase (Ki = 0.50 nM) and prostaglandin release (Ki = 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA2 = 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor. The American Society for Pharmacology and Experimental Therapeutics ER -