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Differential Sensitivity And Mechanism Of Inhibition Of COX-2 Oxygenation Of Arachidonic Acid And 2-Arachidonoylglycerol By Ibuprofen And Mefenamic Acid†

J. J. Prusakiewicz, Kelsey C. Duggan, C. Rouzer, L. Marnett
Published 2009 · Chemistry, Medicine

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Ibuprofen and mefenamic acid are weak, competitive inhibitors of cyclooxygenase-2 (COX-2) oxygenation of arachidonic acid (AA) but potent, noncompetitive inhibitors of 2-arachidonoylglycerol (2-AG) oxygenation. The slow, tight-binding inhibitor, indomethacin, is a potent inhibitor of 2-AG and AA oxygenation whereas the rapidly reversible inhibitor, 2′-des-methylindomethacin, is a potent inhibitor of 2-AG oxygenation but a poor inhibitor of AA oxygenation. These observations are consistent with a model in which inhibitors bind in one subunit of COX-2 and inhibit 2-AG binding in the other subunit of the homodimeric protein. In contrast, ibuprofen and mefenamate must bind in both subunits to inhibit AA binding.
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