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Allosteric Inhibition of [125I] ET-1 Binding to ETA Receptors by Aldoxime and Hydroxamic Acid Derivatives

[ Vol. 4 , Issue. 4 ]


Musa Ahmed, Susanna Nencetti, Maria R. Mazzoni, Francesca Porchia, Federica Antonelli and Annalina Lapucci   Pages 298 - 308 ( 11 )


Endothelin-1 (ET-1), a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ETB. An unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid (SA) are allosteric inhibitors of ET-1 binding to ETA receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, disubstituted benzohydroxamic acid, benzaldoximes and dihalosalicylic acid dimers were synthesized and tested as inhibitors of [125 I]ET-1 binding to ETA receptors in rat embryonic cardiomyocyte (H9c2 cell) membranes. Some dihalosalicylic acid dimers 2h showed good inhibitory activity, the most active compounds are the hydroxamic acids derived from anthranilic acid. Among these compounds, the 3, 5-diiodo-2-aminobenzohydroxamic acid e compound 2a is three-folds more potent as inhibitor of [125I] ET-1 binding to ETA receptors than the 3; 5-diiodosalicylic acid reported in literature. Most aryl aldoximes in this study were biologically inactive as inhibitors of [125I] ET-1 binding to ETA receptors.


Allosteric, endothelin-1, hydroxamic acid, benzaldoxime, 3, 5-diiodo-2-aminobenzohydroxamic acid, 3, 5-diiodosalicylic acid, salicylic acid dimers, ETA receptors


Department of Pharmaceutical Chemistry, Garyounis University, Benghazi, Libya.

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