Monoacylglycerol lipase (MAGL) inhibitors based on a diphenylsulfide-benzoylpiperidine scaffold
Giulia BononiGiacomo TonariniGiulio PoliIvana BarravecchiaIsabella CaligiuriMarco MacchiaFlavio RizzolioGian Carlo DemontisFilippo MinutoloCarlotta GranchiTiziano Tuccinardi
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Diacylglycerol lipase
2-Arachidonoylglycerol
Anandamide
Diacylglycerol lipase
Placentation
Palmitoylethanolamide
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Diacylglycerol lipase
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The endocannabinoid system includes signaling ligands for the cannabinoid receptors, (CB1, CB2) as well as the enzymes that that are responsible for their biosynthesis and degradation. The two primary endogenous ligands N-arachidonoylethanolamine (AEA) and (2-AG) interact with the CB receptors similar to Δ9-tetrahydrocannabinol (THC), a classical cannabinoid isolated from the Cannabis sativa plant. The endocannabinoids AEA and 2-AG are released "on demand" by neurons in the brain as well as in peripheral tissues. Manipulating the concentration of these signaling molecules is an important area of investigation as significant therapeutic benefits are anticipated.
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Diacylglycerol lipase
2-Arachidonoylglycerol
Retrograde signaling
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Abstract 2‐Arachidonoylglycerol (2‐AG) is a monoacylglycerol (MAG) molecule containing an esterified arachidonic acid chain at sn‐2 position of the glycerol backbone. Together with structurally similar N ‐arachidonoylethanolamine (anandamide), 2‐AG has been extensively studied as an endogenous ligand of cannabinoid receptors (an endocannabinoid) in brain and other mammalian tissues. Accumulating evidence demonstrates that the endocannabinoid system, including the central‐type cannabinoid receptor CB1 and 2‐AG, is responsible for synaptic retrograde signaling in the central nervous system. As 2‐AG is rapidly formed from membrane phospholipids on cellular stimuli and degraded to arachidonic acid and glycerol, the enzymes catalyzing its biosynthesis and degradation are believed to play crucial roles in the regulation of its tissue levels. The major biosynthetic pathway appears to consist of sequential hydrolyses of inositol phospholipids via diacylglycerol (DAG) by β‐type phospholipase C and DAG lipase, while MAG lipase is a principal enzyme in the degradation. In this short review, we will briefly outline rapid advances in enzymological research on the biosynthetic and degradative pathways of 2‐AG.
2-Arachidonoylglycerol
Diacylglycerol lipase
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Retrograde signaling
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Lipases in the Endocannabinoid System The endocannabinoid system (ECS) is found in the central nervous system (CNS) and includes the cannabinoid receptors CB1 and CB2 [the ‘locks’], the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG)[the ‘keys’], and the enzymes (‘locksmiths’) that make and break down these ‘keys’. Activation of the CB1 and CB2 receptors by the endocannabinoid ligands 2-AG and AEA regulates neurotransmission and neuroendocrine activity in the brain. In the brain, 2-AG is found at levels approximately 170 times higher than that of AEA making it the most abundant endocannabinoid ligand. In mouse models for Parkinson’s disease (PD), it was observed that an increase of 2-AG levels suppressed inflammatory cytokines. The relationship of 2-AG levels to the enzymes that synthesize and degrade it make 2-AG and its enzymes excellent targets for biotherapeutics. In this study, we examine the role of the principal synthetic enzyme, diacylglycerol lipase-ɑ (DAGL-ɑ) and the principal hydrolytic enzyme monoacylglycerol lipase (MAGL). Through studies of these lipases, we hope to provide further insight into 2-AG signaling in disease states. There were two goals of this thesis. The first goal was to elucidate DAGL-ɑ by expressing, purifying, and characterizing its enzymatic activity. We used an SDS-PAGE gel which separates proteins by size and found two bands which we believe represent DAGL-ɑ at~120 and 80 kDa in size. In the future we hope to optimize the purification method so that we have enough DAGL-a to perform structural studies. The second goal was to investigate the mechanisms of activity of MAGL. MAGL is a well characterized enzyme whose structure was solved in 2010. Given that MAGL is responsible for regulating the levels of 2-AG, there is interest in designing inhibitors to MAGL to treat neurodegenerative diseases. In this experiment, we looked at how different changes in the structure will affect the enzyme activity. By identifying interesting changes in activity, we hope to infer on the structural mechanism of MAGL activity. Our results demonstrated a mechanism involving activated states which changes the enzymatic activity of MAGL. By examining these mechanisms, we hope to identify potential drug targets involving MAGL. In summary we believe we have contributed to the understanding of 2-AG regulation by DAGL-ɑ and MAGL which is useful in designing therapies for neurodegenerative diseases. Master’s Degree Project in Molecular Biology 60 credits 2020 Department of Biology, Lund University Advisor: Christian Krintel Lund University/Department of Structural Biology (Less)
Diacylglycerol lipase
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Anandamide
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Recurrent Binge Eating (BE) episodes characterize several eating disorders. Here, we attempted to reassemble a condition closer to BE disorder, and we analyzed whether recurrent episodes might evoke molecular alterations in the hypothalamus of rats. The hypothalamus is a brain region which is sensitive to stress and relevant in motivated behaviors, such as food intake. A well-characterized animal model of BE, in which a history of intermittent food restriction and stress induce binge-like palatable food consumption, was used to analyze the transcriptional regulation of the endocannabinoid system (ECS). We detected, in rats showing the BE behavior, an up-regulated gene expression of cannabinoid type-1 receptor (CB1), sn-1-specific diacylglycerol lipase, as well as fatty acid amide hydrolase (Faah) and monoacylglycerol lipase. A selective reduction in DNA methylation was also observed at the promoter of Faah, which is consistent with the changes in the gene expression. Moreover, BE behavior in rats was associated with an increase in anandamide (AEA) levels. Our findings support the relevant role of the ECS in the regulation of food intake in rats subjected to repeated BE episodes, and, in particular, on AEA signaling, acting via CB1 and FAAH modulation. Notably, the epigenetic regulation of the Faah gene might suggest this enzyme as a possible target for developing new therapeutical approaches.
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Anandamide
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This review describes the development of inhibitors for endocannabinoid metabolism and their potential therapeutic benefit.
Diacylglycerol lipase
2-Arachidonoylglycerol
Anandamide
Cannabinoid receptor antagonist
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The two principal endocannabinoids, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol (2-AG), are synthesized from arachidonic acid (AA) and AA is released as they are degraded. Therefore, the function of endocannabinoids is closely linked to AA, but the exact relationships have not been clarified, especially with respect to endocannabinoid metabolism. In the present study, oil rich in AA was administered (0, 100, 200 and 300 m l) orally to male mice for 7 days. Phospholipase D (PLD), fatty acid amide hydrolase (FAAH), diacyl-glycerol lipase (DAGL), monoacyl-glycerol lipase (MAGL) and cannabinoid 1 (CB1) receptor mRNA expressions were determined in the whole brain. No changes in the expression of any gene investigated were detected following AA treatment. However, it was demonstrated that the expression of the CB1 receptor was positively correlated with PLD, FAAH and DAGL expression. This suggests that expression of the CB1 receptor is closely coordinated with that of the enzymes which synthesize its ligands.
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Diacylglycerol lipase
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Endocannabinoids, defined in 1995 as endogenous agonists of cannabinoid receptors, their anabolic and catabolic pathways, and the enzymes involved in these pathways (the "endocannabinoid enzymes"), are the subject of this review. A general strategy seems to apply to the regulation of the levels of the two major endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG). Five endocannabinoid enzymes have been cloned to date: two are responsible for the biosynthesis and degradation of anandamide, the NAPE-selective phospholipase D and the fatty acid amide hydrolase, respectively; the other three catalyse the biosynthesis and degradation of 2-AG, the sn-1-selective diacylglycerol lipases α and β and the monoacylglycerol lipase, respectively. The major features of these five proteins, their relative weight in determining endocannabinoid levels, and the possible targeting of some of them for therapeutic purpose, as well as the possibility of the existence of alternative anabolic and catabolic pathways are discussed. Keywords: ANANDAMIDE, CANNABINOID RECEPTOR ANTAGONISTS, fatty acid amide hydrolase (FAAH), DAG lipases, MAGL expression, post-synaptic neuron
Anandamide
2-Arachidonoylglycerol
Diacylglycerol lipase
Catabolism
Metabolic pathway
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