Pettibone D J, Clineschmidt B V, Anderson P S, Freidinger R M, Lundell G F, Koupal L R, Schwartz C D, Williamson J M, Goetz M A, Hensens O D
Department of New Lead Pharmacology, Merck, Sharp, and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Endocrinology. 1989 Jul;125(1):217-22. doi: 10.1210/endo-125-1-217.
The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.
描述了从新发现的西尔维链霉菌天然产物（L-156,373）衍生的两种环六肽的体外和体内催产素/精氨酸加压素（OT/AVP）拮抗剂特性。在放射性配体结合试验中，L-156,373 [环（L-脯氨酸-D-苯丙氨酸-N-羟基-L-异亮氨酸-D-哌嗪基-L-哌嗪基-N-甲基-D-苯丙氨酸）]对大鼠子宫OT受体表现出中等亲和力（Ki，150 nM），与肝脏AVP-V1和肾脏AVP-V2受体相比具有一定选择性（约20倍）。L-156-373的N-羟基异亮氨酸脱羟基和哌嗪酸残基氧化产生了一种有趣的衍生物L-365,209。这些结构修饰分别使OT受体亲和力和选择性提高了20倍和2.5至5倍。在离体大鼠子宫中，L-365,209是一种强效（表观解离常数，1.7 nM）竞争性OT拮抗剂。L-365,209还能在低微摩尔浓度下阻断AVP在AVP-V1（大鼠肝细胞中磷脂酰肌醇周转）和AVP-V2（大鼠肾髓质中腺苷酸环化酶）受体上的作用。给麻醉大鼠静脉注射L-365,209可拮抗外源性OT对子宫的作用（ID50，460微克/千克），作用持续时间相对较长。L-365,209代表了一类独特的化合物，为这些神经垂体激素拮抗剂的设计提供了全新的方法。
