CONFORMATIONAL RESTRICTION OF ANGIOTENSIN-II - CYCLIC ANALOGS HAVING HIGH POTENCY

被引：61

作者：

SPEAR, KL ^{[1
]}

BROWN, MS ^{[1
]}

REINHARD, EJ ^{[1
]}

MCMAHON, EG ^{[1
]}

OLINS, GM ^{[1
]}

PALOMO, MA ^{[1
]}

PATTON, DR ^{[1
]}

机构：

[1] MONSANTO CO, GD SEARLE & CO, DEPT CARDIOVASC DIS RES, DIV SEARLE RES & DEV, CHESTERFIELD, MO 63198 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1990年 / 33卷 / 07期

关键词：

D O I：

10.1021/jm00169a019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cyclic analogues of angiotensin II (All) were synthesized by connecting the side chains of residues 3 and 5 via a disulfide bridge. Appropriate conformational constraints afforded an analogue, [Hcy3,5] All, having high contractile activity (pD2 = 8.48 vs 8.81 for All) and excellent binding affinity (IC50 = 2.1 nM vs 2.2 nM for All). This type of cyclization was also used to prepare a highly potent All antagonist, [Sar1,Hcy3’5,Ile8]AII (pA2 = 9.09 vs 9.17 for [Sar1,Ile8]All; 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 7-turn. In contrast, the receptor-bound conformation of All does not appear to accommodate a β-turn or an a-helix which includes residues 3–5. © 1990, American Chemical Society. All rights reserved.

引用

页码：1935 / 1940

页数：6

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