title: (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2.
abstract: 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.
authors: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Kelsey C
authors: KC
authors: Duggan
authors: Daniel J
authors: DJ
authors: Hermanson
authors: Joel
authors: J
authors: Musee
authors: Jeffery J
authors: JJ
authors: Prusakiewicz
authors: Jami L
authors: JL
authors: Scheib
authors: Bruce D
authors: BD
authors: Carter
authors: Surajit
authors: S
authors: Banerjee
authors: J A
authors: JA
authors: Oates
authors: Lawrence J
authors: LJ
authors: Marnett
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D005989:Glycerides; D016718:Arachidonic Acid; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2