TY - JOUR T1 - Identification of an orally active, nonpeptidyl oxytocin antagonist. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 308 LP - 314 VL - 264 IS - 1 AU - D J Pettibone AU - B V Clineschmidt AU - M T Kishel AU - E V Lis AU - D R Reiss AU - C J Woyden AU - B E Evans AU - R M Freidinger AU - D F Veber AU - M J Cook Y1 - 1993/01/01 UR - http://jpet.aspetjournals.org/content/264/1/308.abstract N2 - L-366,509, a member of a novel class of nonpeptidyl compounds, has been characterized as an orally active oxytocin (OT) antagonist. L-366,509 exhibits a moderate binding affinity (K(i) values, 370-780 nM) for the rat, rhesus and human uterine OT receptor. L-366,509 also binds to vasopressin receptor subtypes (arginine vasopressin-V1 and V2) with measurable affinity in rat (K(i) values, 25-30 microM) and primate (K(i) values, 2-6 microM) tissues. In rat uterine slices, L-366,509 inhibits (IC50 = 1.6 microM) the stimulation of phosphatidylinositol turnover induced by OT but not bradykinin. In the rat isolated uterus, L-366,509 is a competitive and reversible OT antagonist (pA2 = 7.32). In vivo, L-366,509 given i.v. (10 mg/kg) or intraduodenally (10-50 mg/kg) to rats causes a marked and long-lasting inhibition of OT-stimulated uterine activity. OT antagonist activity in a pregnant rhesus macaque (approximately day 135 gestation) is also observed with L-366,509 after i.v. or p.o. dosing. L-366,509 represents a prototype for a new chemical class of OT antagonists with significant p.o. bioavailability. ER -