(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2.

Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, Banerjee S, Oates JA, Marnett LJ
Nat Chem Biol. 2011 7 (11): 803-9

PMID: 22053353 · PMCID: PMC3298755 · DOI:10.1038/nchembio.663

Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid and the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. Evaluation of a series of COX-2 inhibitors revealed that many weak competitive inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation. (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are considered to be inactive as COX-2 inhibitors, are potent 'substrate-selective inhibitors' of endocannabinoid oxygenation. Crystal structures of the COX-2–(R)-naproxen and COX-2–(R)-flurbiprofen complexes verified this unexpected binding and defined the orientation of the (R) enantiomers relative to (S) enantiomers. (R)-Profens selectively inhibited endocannabinoid oxygenation by lipopolysaccharide-stimulated dorsal root ganglion (DRG) cells. Substrate-selective inhibition provides new tools for investigating the role of COX-2 in endocannabinoid oxygenation and a possible explanation for the ability of (R)-profens to maintain endocannabinoid tone in models of neuropathic pain.

MeSH Terms (14)

Arachidonic Acid Arachidonic Acids Cannabinoid Receptor Modulators Catalytic Domain Chemistry, Pharmaceutical Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Endocannabinoids Glycerides Models, Molecular Oxidation-Reduction Protein Binding Protein Conformation Substrate Specificity

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