4-Chloro-3-[(3R)-(ϩ)-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 (K i ϭ 0.44 nM) and exhibited much lower affinity for V 1a , V 1b , and V 2 receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 M). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I 125 ]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 Ca 2ϩ increase (K i ϭ 0.50 nM) and prostaglandin release (K i ϭ 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA 2 ϭ 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.Preterm labor (at less than 37 completed weeks of gestation) occurs in approximatively 10% of births, accounts for 70% of all neonatal mortality and morbidity, and represents one of the highest costs per patient in health care budgets. Even though survival of preterm infants has increased due to the development of neonatal intensive care units, there has been no decrease in the rate of premature birth in the past 30Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.061200.
ABBREVIATIONS:OT, oxytocin; AVP, arginine vasopressin; OTR, oxytocin receptor; SSR126768A, 4-chloro ; ANOVA, analysis of variance; IUP, intrauterine pressure.
