Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation.
Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of the canonical eCB inactivation pathways - fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-arachidonoylglycerol. We review here the experimental evidence that cyclooxygenase-2 (COX-2)-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of 'substrate-selective' COX-2 inhibitors (SSCIs) that prevent eCB inactivation by COX-2 without affecting prostaglandin (PG) generation from arachidonic acid (AA). Lastly, we review recent data on the potential therapeutic applications of SSCIs with a focus on neuropsychiatric disorders.
A.B. Hancock Jr Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology Center in Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Daniel J
DJ
Hermanson
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Joyonna C
JC
Gamble-George
A.B. Hancock Jr Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology Center in Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: larry.marnett@vanderbilt.edu.
Lawrence J
LJ
Marnett
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: sachin.patel@vanderbilt.edu.
Sachin
S
Patel
D000818:Animals; D002186:Cannabinoids / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity
D002186:Cannabinoids; D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2