AT(4) RECEPTOR STRUCTURE-BINDING RELATIONSHIP - N-TERMINAL-MODIFIED ANGIOTENSIN-IV ANALOGS

The effect of structural changes in the N-terminal amino acid of AIV, with respect to AT(4) receptor binding, was examined by competition wi th [I-125]AIV in bovine adrenal membranes. Analogues with modification s of the first residue alpha-amino group possessed lower affinities th an the primary amine-containing parent compound. Peptides with a resid ue 1 alpha-carbon in the D conformation exhibited poor affinity for th e AT(4) receptor. Modifications of the residue 1 R-group demonstrate t hat a straight chain aliphatic moiety containing four carbons is optim al for receptor-ligand binding, as evidenced by the extremely high aff inity of[Nle(1)]AIV (K-i = 3.59 +/- 0.51 pM). Replacement of the 1-2 p eptide bond of AIV with the methylene bond isostere psi (CH2-NH), incr eased the K-i approximately fivefold, indicating that the peptide bond may be replaced while maintaining relatively high-affinity receptor b inding.