Structure-activity relationships for the competitive angiotensin antagonist [sarcosine,O-methyltyrosine4]angiotensin...

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(Me)4]ANG II (sarmesin) in which the sarcosine-1, O-methyltyrosine-4, and phenylalanine-8 residues were modified have been synthesized by the solid-phase method. The agonist and antagonist potencies of the 23 peptides synthesized were determined in the rat isolated uterus assay. At position 1, replacement of Sar with Asp, Ala, or Pro gave inactive analogues, and deletion of the N-terminal amino acid produced inactive heptapeptides for all analogues investigated. At position 4, substitution of Tyr with Tyr(Et), D-Tyr, D-Phe, Ile, Thr, or Hyp resulted in inactive analogues, whereas substitution of Phe gave a potent competitive antagonist (pA2 = 7.9), which retained significant agonist activity (22%). For position 8, [Sar1,Tyr(Me)4,Ile8]ANG II and [Sar1,Phe4,Ile8]ANG II were weaker antagonists (pA2 = 6.6 and 6.7, respectively) than [Sar1,Ile8]ANG II (pA2 apparent = 8.1) and, moreover, were reversible competitive antagonists. These findings demonstrate that the structural requirements for receptor blockade by sarmesin are remarkably stringent--modifications at positions 1, 4, and 8 markedly reduce the antagonist activity of this peptide.