Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects
By Jonathan Z. Long, Weiwei Li, L. Booker, J. Burston, S. Kinsey, J. Schlosburg, F. J. Pavón, A. Serrano, D. Selley, L. Parsons and 2 more. Nature Chemical Biology, 2008
922 citations recorded by the source corpus.
2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for anandamide, is mediated by fatty acid amide hydrolase (FAAH) and, for 2-AG, is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, intimating a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL, JZL184, that, upon administration to mice, raises brain 2-AG by 8-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia, and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.
Subfields: Cognitive Neuroscience, Pharmacology, Toxicology
View Paper: https://www.semanticscholar.org/paper/8b9809bd2e5efe08b8d2d53a99c4d3c7c6042a21
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Pharmacology
In Toxicology
Citations in the corpus
- The pharmacological landscape and therapeutic potential of serine hydrolases (2012, background): “Following on the success of rivastigmine, carbamates have emerged as a versatile chemotype for serine hydrolase inhibitors, as embedding this tempered reactive group into various structural scaffolds has led to the generation of selective inhibitors for several serine hydrolase”
- Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis (2010, methodology): “The key role that MAGL plays in regulating FFA levels in aggressive cancer cells contrasts with the function of this enzyme in normal tissues, where it mainly controls the levels of MAGs, but not FFAs (Long et al., 2009b).”
- Neuroactive insecticides: targets, selectivity, resistance, and secondary effects. (2013, background): “Selective and reversible carbamate FAAH and MAGL inhibitors have been designed with the goal of pain relief (88).”