Importance of the N-terminal domain of the type II angiotensin antagonist sarmesin for receptor blockade

Abstract

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(Me)4]angiotensin II (sarmesin) with modifications at the N-terminus have been prepared by the solid-phase method and purified by reversed-phase HPLC. Substitution of the Sar1 residue of sarmesin with N,N-dimethyl-Gly, N-ethyl-Gly, aminoisobutyric, (methylamino)isobutyric, aminocarproic,and oxamic acids gave analogues that had the following respective antagonist activities (pA2) in the rat isolated uterus assay: < 6, 6.9, 5.5, 6.0, < 6, and 5.3. The additional substitution of Ile for Phe at the C-terminus of the latter four peptides gave pA2 values of 7.1, 5.1 < 5, and 5. Substitution of the Arg2 residue of sarmesin with Nle or Sar abolished antagonist activity. These data emphasize the stringent and discriminating structural requirements in the N-terminal domain of sarmesin that endow this analogue with its antagonist properties and suggest the presence of defined steric constraints in this region of the molecule during receptor blockade.