The importance of residues 2 (arginine) and 6 (histidine) in high-affinity angiotensin II antagonists

J Samanen; E Brandeis; D Narindray; W Adams; T Cash; T Yellin; D Regoli

doi:10.1021/jm00399a008

The importance of residues 2 (arginine) and 6 (histidine) in high-affinity angiotensin II antagonists

J Med Chem. 1988 Apr;31(4):737-41. doi: 10.1021/jm00399a008.

Authors

J Samanen¹, E Brandeis, D Narindray, W Adams, T Cash, T Yellin, D Regoli

Affiliation

¹ Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, Pennsylvania 19479.

PMID: 3351849
DOI: 10.1021/jm00399a008

Abstract

The structure-antagonist activity relationship is described for analogues of [Sar1,Ile8]angiotensin II substituted in position 2 (arginine) and position 6 (histidine). An extreme sensitivity of potency to alterations in these positions was observed, suggesting that both residues are important for binding. Evidence is presented suggesting that the position 6 histidine side chain in angiotensin II (AII) is not involved in receptor stimulation. The structure-activity relationship is also explored for both [des-Asp1] AII (AIII) and [des-Asp1,Ile8]AII analogues substituted in position 2 (arginine). The substitution of D-N-methylalanine, D-(NMe)Ala, into position 2 of both [des-Asp1]AII and [des-Asp1,Ile8]AII gives analogues 39 and 40 that appear to be more potent than the native [Arg2]peptides and that are the most potent AIII agonists and antagonists described to date.

MeSH terms

Angiotensin II / analogs & derivatives*
Angiotensin II / antagonists & inhibitors*
Angiotensin II / pharmacology
Animals
Arginine*
Blood Pressure / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Histidine*
Muscle, Smooth, Vascular / drug effects
Rabbits
Rats
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Angiotensin II
Histidine
angiotensin II, Sar(1)-Ile(5)-
Arginine