血管紧张素II的构象限制：具有高效力的环状类似物。

Conformational restriction of angiotensin II: cyclic analogues having high potency.

作者信息

Spear K L, Brown M S, Reinhard E J, McMahon E G, Olins G M, Palomo M A, Patton D R

机构信息

Cardiovascular Diseases Research Department, G. D. Searle and Company, c/o Monsanto Company, Chesterfield, Missouri 63198.

出版信息

J Med Chem. 1990 Jul;33(7):1935-40. doi: 10.1021/jm00169a019.

DOI:10.1021/jm00169a019

PMID:2362273

Abstract

Cyclic analogues of angiotensin II (AII) were synthesized by connecting the side chains of residues 3 and 5 via a disulfide bridge. Appropriate conformational constraints afforded an analogue, [Hcy3,5]AII, having high contractile activity (pD2 = 8.48 vs 8.81 for AII) and excellent binding affinity (IC50 = 2.1 nM vs 2.2 nM for AII). This type of cyclization was also used to prepare a highly potent AII antagonist, [Sar1,Hcy3,5,Ile8]AII (pA2 = 9.09 vs 9.17 for [Sar1, Ile8]AII; IC50 = 0.9 nM vs 1.9 nM for [Sar1,Ile8]AII). Model building suggests that this ring structure is consistent with a receptor-bound conformation having any of a variety of three-residue turns, including a gamma-turn. In contrast, the receptor-bound conformation of AII does not appear to accommodate a beta-turn or an alpha-helix which includes residues 3-5.

摘要

通过二硫键连接残基3和5的侧链合成了血管紧张素II（AII）的环状类似物。适当的构象限制产生了一种类似物[Hcy3,5]AII，其具有高收缩活性（pD2 = 8.48，而AII为8.81）和优异的结合亲和力（IC50 = 2.1 nM，而AII为2.2 nM）。这种环化类型还用于制备一种高效的AII拮抗剂[Sar1,Hcy3,5,Ile8]AII（pA2 = 9.09，而[Sar1, Ile8]AII为9.17；IC50 = 0.9 nM，而[Sar1,Ile8]AII为1.9 nM）。模型构建表明，这种环结构与具有多种三残基转角（包括γ-转角）中任何一种的受体结合构象一致。相比之下，AII的受体结合构象似乎不包含β-转角或包含残基3-5的α-螺旋。