Conformational restriction of angiotensin II: cyclic analogs having high potency

• Published in: Journal of medicinal chemistry 1990-07, Vol.33 (7), p.1935-1940
• Main Authors: Spear, Kerry L, Brown, Monica S, Reinhard, Emily J, McMahon, Ellen G, Olins, Gillian M, Palomo, Maria A, Patton, Dennis R
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Angiotensin II - analogs & derivatives; Angiotensin II - chemical synthesis; Angiotensin II - pharmacology; Animals; Aorta - drug effects; Aorta - physiology; Cell Membrane - metabolism; Female; In Vitro Techniques; Molecular Sequence Data; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - pharmacology; Protein Conformation; Rabbits; Rats; Receptors, Angiotensin - drug effects; Receptors, Angiotensin - metabolism; Structure-Activity Relationship; Uterus - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00169a019

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.