Conformational restriction of angiotensin II: cyclic analogues having high potency.
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.
Spear
K L
KL
Cardiovascular Diseases Research Department, G. D. Searle and Company, c/o Monsanto Company, Chesterfield, Missouri 63198.
Brown
M S
MS
Reinhard
E J
EJ
McMahon
E G
EG
Olins
G M
GM
Palomo
M A
MA
Patton
D R
DR
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000378:metabolism
D010456:Peptides, Cyclic; D011945:Receptors, Angiotensin; D000804:Angiotensin II