Identification of an orally active, nonpeptidyl oxytocin antagonist.

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.

Radioligand binding studies reveal marked species differences in the vasopressin V1 receptor of rat, rhesus and human tissues.

The [3H]arginine-vasopressin ([3H]AVP) binding site in rat, rhesus and human liver and nonpregnant human uterus was characterized and contrasted. [3H]AVP bound with high affinity (Ki values, 0.2-0.6 nM) to preparations of all tissues studied. Competition binding studies using a series of compounds from three structural classes indicate a marked species difference between the rat and primate liver AVP-V1 site. This site in rhesus and human liver however, is essentially identical, indicating that the rhesus liver is an appropriate surrogate for human tissue. These studies also indicate that the AVP-V1 site of nonpregnant human uterus and human liver is equivalent.