Synthesis and Biological Activities of Analogues of Angiotensins II and III Containing O-Methyltyrosine and D-Tryptophan

Article abstract of DOI:10.1021/jm00383a015

Analogues of angiotensin II and III (ANG II and ANG III) in which the tyrosine and/or phenylalanine residues were substituted have been synthesized by the solid-phase method and purified by (carboxymethyl)cellulose chromatography and reversed-phase HPLC.The antagonist and agonist potencies of these peptide were determined in the rat isolated uterus assay. 1,Tyr(Me)⁴>ANG II, 3>ANG III, 1,D-Trp⁴>ANG II, 3>ANG III, 1,D-Trp⁸>ANG II, 7>ANG III, 1,Tyr(Me)⁴,Ile⁸>ANG II, 3,Ile⁷>ANG III, 1,D-Trp⁴,Ile⁸>ANG II, 3,Ile⁷>ANG III, 1,Tyr((Me)⁴,D-Trp⁸>ANG II, and 3,D-Trp⁷>ANG III had antagonist activities (pA₂) respectively of 8.1, <6, <6, <6, (7.7), (6.7), 7.2, <6, <6, <6, 7.1, and <6.The agonist activity of each peptide was less than 0.1percent of that of ANG II.Analogues in which only the Phe residue was subtituted were not readily reversible in the bioassay, whereas analogues in which only by the Tyr residue or both the Tyr and Phe residues were substituted were reversible antagonists.Peptides that were twice substituted had lower antagonist activities than peptides having a single aromatic residue substitution.Substitution of the Tyr residue in ANG II, but not ANG III, provides a new route for the synthesis of potent and competitive angiotensin antagonists.Differences in the biological properties of ANG II and ANG III analogues substituted at the Tyr residue suggest different binding/conformation requirements for the two endogenous ligands at angiotensin receptors in smooth muscle.