Manning M, Stoev S, Cheng L L, Wo N C, Chan W Y
Department of Biochemistry & Molecular Biology, Medical College of Ohio, Toledo 43614, USA.
J Recept Signal Transduct Res. 1999 Jan-Jul;19(1-4):631-44. doi: 10.3109/10799899909036676.
This presentation will trace the serendipitous discovery of novel vasopressin (VP) hypotensive agonists d(CH2)5[D-Tyr(Et)2,X3]VAVP (where X = Arg, Lys). These peptides were uncovered as part of an ongoing program aimed at the design of potent and selective VP antidiuretic (V2 receptor) antagonists. We will also present highlights of our subsequent preliminary studies seeking (i) to design high affinity radioiodinatable ligands for the localization and characterization of the putative VP vasodilatory (V1c?) receptor; (ii) to identify the structural features of selective and non-selective cyclic and linear VP and oxytocin (OT) antagonists of the V2 receptor, the vascular (V1a) receptor and of the uterine (OT) receptor required for hypotensive agonism and; (iii) to enhance hypotensive potency. These novel VP hypotensive agonists could serve as valuable research tools in studies on the roles of VP in blood pressure regulation and may also lead to the development of a new class of therapeutically useful antihypertensives.
本报告将追溯新型血管加压素（VP）降压激动剂d(CH2)5[D-Tyr(Et)2,X3]VAVP（其中X = Arg，Lys）的偶然发现。这些肽是作为一个正在进行的项目的一部分被发现的，该项目旨在设计强效且选择性的VP抗利尿（V2受体）拮抗剂。我们还将展示后续初步研究的亮点，这些研究旨在：（i）设计高亲和力的可放射性碘化配体，用于假定的VP血管舒张（V1c？）受体的定位和表征；（ii）确定V2受体、血管（V1a）受体和子宫（OT）受体的选择性和非选择性环状及线性VP和催产素（OT）拮抗剂的结构特征，这些特征是降压激动作用所必需的；以及（iii）提高降压效力。这些新型VP降压激动剂可作为研究VP在血压调节中作用的有价值的研究工具，也可能导致开发一类新的具有治疗用途的抗高血压药物。
