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

Area of Science:

• Biochemistry
• Pharmacology
• Neuroscience

Background:

• Cyclooxygenase-2 (COX-2) is an enzyme involved in the metabolism of arachidonic acid and endocannabinoids.
• Endocannabinoids play crucial roles in pain signaling and modulation.
• The role of COX-2 in endocannabinoid metabolism is not fully understood.

Purpose of the Study:

• To investigate the inhibitory effects of COX-2 inhibitors on endocannabinoid oxygenation.
• To explore the substrate selectivity of COX-2 inhibitors.
• To understand the mechanism behind the pain-relieving effects of (R)-profens.

Main Methods:

• Evaluation of a series of COX-2 inhibitors.
• Analysis of substrate selectivity for arachidonic acid versus endocannabinoids.
• X-ray crystallography of COX-2 inhibitor complexes.
• Inhibition assays using lipopolysaccharide-stimulated dorsal root ganglion (DRG) cells.

Main Results:

• Many weak inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation.
• (R)-enantiomers of ibuprofen, naproxen, and flurbiprofen (profens), previously considered inactive, are potent 'substrate-selective inhibitors' of endocannabinoid oxygenation.
• Crystal structures confirmed the binding of (R)-profens to COX-2.
• (R)-Profens selectively inhibited endocannabinoid oxygenation in DRG cells.

Conclusions:

• Substrate-selective inhibition of endocannabinoid oxygenation by (R)-profens provides novel research tools.
• This finding offers a potential explanation for the therapeutic effects of (R)-profens in neuropathic pain models.
• Further research into COX-2's role in endocannabinoid metabolism is warranted.