AT4 receptor structure-binding relationship: N-terminal-modified angiotensin IV analogues

Abstract

The effect of structural changes in the N-terminal amino acid of AIV, with respect to AT4 receptor binding, was examined by competition with [125I]AIV in bovine adrenal membranes. Analogues with modifications of the first residue α-amino group possessed lower affinities than the primary amine-containing parent compound. Peptides with a residue 1 α-carbon in the d conformation exhibited poor affinity for the AT4 receptor. Modifications of the residue 1 R-group demonstrate that a straight chain aliphatic moiety containing four carbons is optimal for receptor-ligand binding, as evidenced by the extremely high affinity of [Nle1]AIV (Ki = 3.59±0.51 pM). Replacement of the 1-2 peptide bond of AIV with the methylene bond isostere Ψ (CH2-NH), increased the Ki approximately fivefold, indicating that the peptide bond may be replaced wihle maintaining relatively high-affinity receptor binding. © 1994.