The importance of residues 2 (arginine) and 6 (histidine) in high-affinity angiotensin II antagonists.
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.
Samanen
J
J
Peptide Chemistry Department, Smith Kline and French Laboratories, Swedeland, Pennsylvania 19479.
Brandeis
E
E
Narindray
D
D
Adams
W
W
Cash
T
T
Yellin
T
T
Regoli
D
D
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001120:Arginine; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006639:Histidine; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D000804:Angiotensin II; D006639:Histidine; C032651:angiotensin II, Sar(1)-Ile(5)-; D001120:Arginine