Allosteric inhibition of [[125]I] ET-1 binding to ETA receptors by salicylic acid dimers

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, 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 in aim to development of new potential allosteric inhibitors of ET-1. Some dihalo- salicylic acid dimers synthesized in this study showed promising activity as inhibitor of [[125]I] ET-1 binding to ETA receptors in comparing with the dihalosalicylic acid reported in literature, the bromo substituted compound B showed very interesting activity than other halogen substituted dimers, it causes about 40% inhibition at 100 microM and causes 100% inhibition at 500 microM. we conclude that dihalosalicylic acid dimers can mediate good inhibition activity in comparison to sole dihalosalicylic acid molecule

Inhibition of [[125]I] ET-1 binding to ETA receptors by salicylic acid dimers

Endothelin-1 [ET-1], a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ATB. A 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, 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 in aim to development of new potential allosteric inhibitors of ET-1. Some dihalosalicylic acid dimers synthesized in this study showed promising activity as inhibitor of [[125]I] ET-1 binding to ETA receptors in comparing with the dihalosalicylic acid reported in literature. The bromo substituted compound b showed more remarkable activity than other halogen substituted dimers, it causes about 40% inhibition at 100 microM and causes 100% inhibition at 500 microM. We conclude that dihalosalicylic acid dimers can mediate good inhibition activity in comparison to sole dihalosalicylic acid molecule