Synthesis and biological activity of N-terminus modified [Ile8] angiotensin II analogues

Abstract

Semi-peptidic analogues of the angiotensin II (AII) antagonist [Ile8] AII have been prepared by the solid phase method and, for some steps, by synthesis in solution. In the modified analogues 4–15, the N-terminal di- or tripeptidic fragments (Asp-Arg or Asp-Arg-Val) in [Ile8]AII was replaced by non-peptidic moieties featuring amino or guanidino groups as substituent of simple alkyl spacers of various lengths. The compounds synthesized have been tested for their ability to produce an AII-like contraction and/or to inhibit AII-induced contractions in isolated rabbit aortae. All of them were found devoid of agonistic activity and most retained significant antagonistic activity in this assay. Analogue 5 antagonized AII-induced blood pressure effect in the anesthetized rat when infused at 30 μg/kg/min. The structure-activity relationships for these compounds are discussed.