Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels

Abstract

The structure-activity relationships of organophosphorus (OP) and organosulfur compounds were examined in vitro and in vivo as inhibitors of mouse brain monoacylglycerol lipase (MAGL) hydrolysis of 2-arachidonoylglycerol (2-AG) and agonist binding at the CB1 receptor. Several compounds showed exceptional potency towards MAGL activity with IC 50 values of 0.1-10 nM in vitro and high inihibition at 10 mg/kg intraperitoneally in mice. We find for the first time that MAGL activity is a major in vivo determinant of 2-AG and arachidonic acid levels not only in brain but also in spleen, lung and liver. Apparent direct OP inhibition of CB1 agonist binding may be due instead to metabolic stabilization of 2-AG in brain membranes as the actual inhibitor. Keywords Monoacylglycerol lipase inhibitors; 2-Arachidonoylglycerol; Arachidonic acidThe endocannabinoids (EC) 2-arachidonoylglycerol (2-AG) and anandamide (AEA) regulate a diverse array of neurological and metabolic functions and are altered by neuropathic pain, anxiety, neurodegeneration, obesity and cardiovascular disorders. 1 2-AG is a full agonist towards the cannabinoid receptor type 1 (CB1) and its signaling is terminated primarily by monoacylglycerol lipase (MAGL). AEA levels are regulated by fatty acid amide hydrolase (FAAH). 2-4 Augmentation of EC signaling by blockade of 2-AG or AEA degradation (Scheme 1) is proposed as a therapeutic strategy. However, characterization of MAGL or 2-AG in brain and peripheral tissues is hindered by the paucity of systemic MAGL inhibitors and lack of a MAGL knockout mouse. Discovery of potent MAGL inhibitors is therefore essential in understanding the biochemical, physiological and therapeutic roles of this enzyme.Structural manipulation of organophosphorus (OP) and organosulfur (OS) compounds (Scheme 2) can potentially confer potency and selectivity for MAGL and FAAH compared to * Corresponding author. Tel.: +1 510 642 5424; fax: +1 510 642 6497. E-mail address: ectl@nature.berkeley.edu (J.E. Casida). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. This study reports structure-activity relationships of OPs and OSs with MAGL, FAAH and CB1 and uses these tools to consider three interrelationships of the EC system components. The first is the in vitro potency for inhibiting MAGL, FAAH and CB1 agonist binding as a predictor of in vivo behavioral effects and pharmacological profile. The second is the variation among tissues in their MAGL activity and differential regulation of 2-AG and AA levels. Finally we consider the possibility that OP displacement of CB1 agonist binding is due to 2...

Distribution and function of monoacylglycerol lipase in the gastrointestinal tract

“…These studies indicate MGL plays an important role in lipid regulation and metabolism. Nomura and coworkers (36) recently reported potent inhibition of MGL using organophosphorus (OP) compounds. In their assay, OP inhibition of MGL resulted in increased 2-AG levels and decreased arachidonic acid levels, which in the gut would have anti-inflammatory properties.…”

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease

“…The level of these endocannabinoids (eCB) in the central nervous system (CNS) is influenced by two catabolic enzymes, FAAH and monoacylglycerol lipase (MAGL) (Cravatt et al, 1996;Nomura et al, 2008). Selective and efficacious inhibitors of FAAH and MAGL have been developed, and they produce a specific increase in eCB concentrations in vivo (Fegley et al, 2005;Long et al, 2009).…”

Assay and Inhibition of the Purified Catalytic Domain of Diacylglycerol Lipase Beta

“…In the adult two forms of plasticity are controlled by DAGL-dependent eCB signalling and these are synaptic plasticity in the form of retrograde synaptic transmission throughout the brain 7,8 and cellular plasticity in the form of adult neurogenesis in the hippocampus and sub-ventricular zone 1,7,9,10 . The DAGLs have a second important function, and this is the generation of 2-AG as a substrate for monoacylglycerol lipase (MAGL) to maintain arachidonic acid (AA) levels in various tissues including the brain, liver and adipose 7,11,12 .…”