AT4 receptor structure-binding relationship: N-terminal-modified angiotensin IV analogues.
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 alpha-amino group possessed lower affinities than the primary amine-containing parent compound. Peptides with a residue 1 alpha-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 psi (CH2-NH), increased the Ki approximately fivefold, indicating that the peptide bond may be replaced while maintaining relatively high-affinity receptor binding.
Sardinia
M F
MF
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman 99164-6520.
Hanesworth
J M
JM
Krishnan
F
F
Harding
J W
JW
D000311:Adrenal Glands / Q000378:metabolism*; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship
C090830:AT4 receptor; D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-