Photoaffinity labeling of the angiotensin II receptor; pharmacology of the labeling peptides in the dark

Abstract

The biological activities of photoaffinity labeling analogs of angiotensin II (AT_II) and their precursors were measured in rabbit aorta strips in the dark. Most of the analogs behave as reversible, specific agonists, one as a competitive inhibitor. The activities are discussed in line with the current view of structural requirements. The modifications consisted of substitutions on the aromatic nuclei of Tyr⁴ and Phe⁸ in [Sar¹]AT_II with (4′-NO₂)Phe, (4′-NH₂)Phe, (4′-N₃)Phe, (4′-N₂+)Phe, and (4′-NH₂-3′, 5′-I₂)Phe. It is shown that the affinity of the AT_II analogs modified in position 4 depends on the electronegativity and not on space-filling properties of the aromatic residue; rising electronegativity lowers the affinity, i.e., [Sar¹, (4′-NO₂)Phe⁴]AT_II has no more measurable activity. Substituting the aromatic side chain in position 8 of [Sar¹]AT_II gives well-binding analogs with intrinsic activities from 0 to 100% and activity seems to depend only on stereochemical requirements. Agonists and partial agonists bear rather small groups like -NH₂, -N₃, -NO₂, and -N₂+. The only antagonist [Sar¹, (4′-NH₂-3′,5′-I₂)Phe⁸]AT_II resembles the antagonist [Sar¹, Leu⁸]AT_II in competitivity and binding.