title: Identification of an orally active, nonpeptidyl oxytocin antagonist.
abstract: 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.
authors.affiliation: Department of New Lead Pharmacology, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: D J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: B V
authors.initials: BV
authors.lastname: Clineschmidt
authors.forename: M T
authors.initials: MT
authors.lastname: Kishel
authors.forename: E V
authors.initials: EV
authors.lastname: Lis
authors.forename: D R
authors.initials: DR
authors.lastname: Reiss
authors.forename: C J
authors.initials: CJ
authors.lastname: Woyden
authors.forename: B E
authors.initials: BE
authors.lastname: Evans
authors.forename: R M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
authors.forename: M J
authors.initials: MJ
authors.lastname: Cook
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D010716:Phosphatidylinositols / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013268:Stimulation, Chemical; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D010716:Phosphatidylinositols; D010880:Piperidines; D013141:Spiro Compounds; C077566:L 366509; D010121:Oxytocin