Samanen, J., Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, PA 19479, United States
Brandeis, E., Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, PA 19479, United States
Narindray, D., Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, PA 19479, United States
Adams, W., Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, PA 19479, United States
Cash, T., Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, PA 19479, United States
Yellin, T., Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, PA 19479, United States
Regoli, D., University of Sherbrooke, Quebec, Que. J1H 5N4, Canada

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. © 1988 American Chemical Society.