Potent angiotensin II antagonists with non-beta-branched amino acids in position 5.
Amino acids with lipophilic side chains that contain more than one functional group on the beta-carbon, i.e. a beta-branched hydrocarbon moiety, are required in position 5 of angiotensin II (AII) analogue with potent agonist activity. This requirement for agonist activity does not follow for AII analogues with potent antagonist activity. Straight-chain amino acids may be substituted into position 5 of [Sar1,X5,Ile8]AII with retention or enhancement of antagonist activity, e.g. (X5,pA2 rabbit aorta) Phe, 9.15; Tyr, 9.6; His, 9.0; Glu,9.0; Nle, 8.85, compared to Ile, 9.1. beta-Branched side chains can still enhance the antagonist activities of [Sar1,X5,Ile8]AII analogues, e.g. X5 = (beta Me)Phe, pA2 = 9.3. An X-ray crystal structure of the Boc-(beta Me)Phe DCHA salt, prepared for the synthesis of [Sar1,-(beta Me)Phe5, Ile8]AII, revealed an S,S configuration of alpha- and beta-carbon atoms. Contrary to previous literature reports, chemical nonequivalence of the deta-protons of Pro was observed in the 1H NMR spectra of [Sar1,X5,Ile8]AII analogues bearing both beta-branched X5 side chains (X5 = Ile) and non-beta-branched X5 side chains (X5 = Ala, His).
Samanen
J
J
Peptide Chemistry Department, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Narindray
D
D
Cash
T
T
Brandeis
E
E
Adams
W
W
Yellin
T
T
Eggleston
D
D
DeBrosse
C
C
Regoli
D
D
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D066298:In Vitro Techniques; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D000804:Angiotensin II