Biochemical pharmacology of total retro-inverso analogues of bradykinin and angiotensin II: Molecular recognition by G-protein-coupled receptors and angiotensin converting enzyme
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Total retro-inverso (TRI) analogues of bradykinin (BK), the B2a-selective kinin antagonist d-Arg0[Hyp3,d-Phe7,Leu8]BK, angiotensin II (AT II) and the AT II antagonist Saralasin ([Sar1,Val5,Ala8]AT II) were prepared by conventional solid-phase synthesis. Molecular recognition of TRI peptidomimetics by G-protein-coupled receptors was studied by competitive radioligand displacement experiments. TRI analogues of d-Arg0[Hyp3,d-Phe7,Leu8]BK specifically bound to the kidney medulla B2a bradykinin receptor with affinities (Kd) ranging from 64 μM to 4 μM. Conversely, TRI analogues of BK, AT II and Saralasin did not bind to either the B2a bradykinin receptor or the rat AT1a AT II receptor, respectively. These studies indicate that the TRI strategy is more compatible with the synthesis of antagonists than ‘agonists’. Three TRI peptidomimetics of d-Arg0[Hyp3,d-Phe7,Leu8]BK were weak inhibitors of angiotensin converting enzyme. All other TRI peptidomimetics had no effect upon ACE activity. These data endorse the utility of the TRI strategy for the synthesis of protease-resistant antagonists of peptide hormones and neuropeptides.
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