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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Authors: | Howl John Wheatley Mark |
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Institution: | (1) School of Biochemistry, University of Birmingham, Edgbaston, B15 2TT Birmingham, U.K. |
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Abstract: | Summary Total retro-inverso (TRI) analogues of bradykinin (BK), the B2a
-selective kinin antagonistd-Arg0Hyp3,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 ofd-Arg0Hyp3,d-Phe7,Leu8]BK specifically bound to the kidney medulla B2a
bradykinin receptor with affinities (K
d
) 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 ofd-Arg0Hyp3,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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Keywords: | agonist antagonist hormone |
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