Pettibone D J, Clineschmidt B V, Kishel M T, Lis E V, Reiss D R, Woyden C J, Evans B E, Freidinger R M, Veber D F, Cook M J
Department of New Lead Pharmacology, Merck Research Laboratories, West Point, Pennsylvania.
J Pharmacol Exp Ther. 1993 Jan;264(1):308-14.
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.
L-366,509是一类新型非肽类化合物的成员，已被表征为一种口服活性催产素（OT）拮抗剂。L-366,509对大鼠、恒河猴和人类子宫OT受体表现出中等结合亲和力（K(i)值，370 - 780 nM）。L-366,509还以可测量的亲和力与大鼠（K(i)值，25 - 30 microM）和灵长类动物（K(i)值，2 - 6 microM）组织中的血管加压素受体亚型（精氨酸血管加压素-V1和V2）结合。在大鼠子宫切片中，L-366,509抑制（IC50 = 1.6 microM）由OT诱导的磷脂酰肌醇周转刺激，但不抑制缓激肽诱导的刺激。在大鼠离体子宫中，L-366,509是一种竞争性和可逆性OT拮抗剂（pA2 = 7.32）。在体内，给大鼠静脉注射（10 mg/kg）或十二指肠内注射（10 - 50 mg/kg）L-366,509会导致对OT刺激的子宫活动产生显著且持久的抑制。静脉注射或口服给药后，在怀孕的恒河猴（妊娠约135天）中也观察到L-366,509的OT拮抗剂活性。L-366,509代表了一类具有显著口服生物利用度的新型OT拮抗剂化学类别的原型。
