Dual inhibition of alpha/beta-hydrolase domain 6 and fatty acid amide hydrolase increases endocannabinoid levels in neurons
(2011) Journal of Biological Chemistry — Vol. 286, n° 33, p. 28723-28728 (2011)
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- Agonists at cannabinoid receptors, such as the phytocannabinoid Δ(9)-tetrahydrocannabinol, exert a remarkable array of therapeutic effects but are also associated with undesirable psychoactive side effects. Conversely, targeting enzymes that hydrolyze endocannabinoids (eCBs) allows for more precise fine-tuning of cannabinoid receptor signaling, thus providing therapeutic relief with reduced side effects. Here, we report the development and characterization of an inhibitor of eCB hydrolysis, UCM710, which augments both N-arachidonoylethanolamine and 2-arachidonoylglycerol levels in neurons. This compound displays a unique pharmacological profile in that it inhibits fatty acid amide hydrolase and α/β-hydrolase domain 6 but not monoacylglycerol lipase. Thus, UCM710 represents a novel tool to delineate the therapeutic potential of compounds that manipulate a subset of enzymes that control eCB signaling.
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Marrs, W. R., Horne, E. A., Ortega-Gutierrez, S., Cisneros, J. A., Xu, C., Lin, Y. H., Muccioli, G., Lopez-Rodriguez, M. L., & Stella, N. (2011). Dual inhibition of alpha/beta-hydrolase domain 6 and fatty acid amide hydrolase increases endocannabinoid levels in neurons. Journal of Biological Chemistry, 286(33), 28723-28728. https://doi.org/10.1074/jbc.M110.202853 (Original work published 2011)