The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Benjamin F Cravatt - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Monoacylglycerol Lipase reduces nicotine withdrawal
British Journal of Pharmacology, 2015Co-Authors: Pretal P. Muldoon, Benjamin F Cravatt, Aron H. Lichtman, Jingchun Chen, J L Harenza, Rehab A. Abdullah, Laura J. Sim-selley, M F Miles, Xiangning Chen, M I DamajAbstract:Background and Purpose Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of Monoacylglycerol Lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored.
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The Monoacylglycerol Lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model
Life Sciences, 2012Co-Authors: Sudeshna Ghosh, Anu Mahadevan, Benjamin F Cravatt, Laura E. Wise, Yugang Chen, Ramesh Gujjar, Aron H. LichtmanAbstract:Aim The present study tested whether the selective Monoacylglycerol Lipase (MAGL) inhibitor JZL184 would reduce allodynia and paw edema in the carrageenan test.
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Monoacylglycerol Lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer
Chemistry & Biology, 2011Co-Authors: Daniel K Nomura, Jonathan Z Long, Anna M. Ward, Donald P. Lombardi, Sherry Niessen, Jae Won Chang, Heather H Hoover, Benjamin F CravattAbstract:Summary Cancer cells couple heightened lipogenesis with lipolysis to produce fatty acid networks that support malignancy. Monoacylglycerol Lipase (MAGL) plays a principal role in this process by converting monoglycerides, including the endocannabinoid 2-arachidonoylglycerol (2-AG), to free fatty acids. Here, we show that MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and that pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. These effects were partially reversed by treatment with fatty acids or a cannabinoid receptor-1 (CB1) antagonist, and fully reversed by cotreatment with both agents. We further show that MAGL is part of a gene signature correlated with epithelial-to-mesenchymal transition and the stem-like properties of cancer cells, supporting a role for this enzyme in protumorigenic metabolism that, for prostate cancer, involves the dual control of endocannabinoid and fatty acid pathways.
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fatty acid amide hydrolase and Monoacylglycerol Lipase inhibitors produce anti allodynic effects in mice through distinct cannabinoid receptor mechanisms
The Journal of Pain, 2010Co-Authors: Steven G. Kinsey, Jonathan Z Long, Benjamin F Cravatt, Andrew H LichtmanAbstract:Abstract The endocannabinoids anandamide and 2-arachidonoylglycerol are predominantly regulated by the respective catabolic enzymes fatty acid amide hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL). Inhibition of these enzymes elevates endocannabinoid levels and attenuates neuropathic pain. In the present study, CB 1 and CB 2 receptor-deficient mice were subjected to chronic constriction injury (CCI) of the sciatic nerve to examine the relative contribution of each receptor for the anti-allodynic effects of the FAAH inhibitor, PF-3845, and the MAGL inhibitor, JZL184. CCI caused marked hypersensitivity to mechanical and cold stimuli, which was not altered by deletion of either the CB 1 or CB 2 receptor, but was attenuated by gabapentin, as well as by each enzyme inhibitor. Whereas PF-3845 lacked anti-allodynic efficacy in both knockout lines, JZL184 did not produce anti-allodynic effects in CB 1 (-/-) mice, but retained its anti-allodynic effects in CB 2 (-/-) mice. These data indicate that FAAH and MAGL inhibitors reduce nerve injury-related hyperalgesic states through distinct cannabinoid receptor mechanisms of action. In conclusion, although endogenous cannabinoids do not appear to play a tonic role in long-term expression of neuropathic pain states, both FAAH and MAGL represent potential therapeutic targets for the development of pharmacological agents to treat chronic pain resulting from nerve injury. Perspective This article presents data addressing the cannabinoid receptor mechanisms underlying the anti-allodynic actions of endocannabinoid catabolic enzyme inhibitors in the mouse sciatic nerve ligation model. Fatty acid amide hydrolase and Monoacylglycerol Lipase inhibitors reduced allodynia through distinct cannabinoid receptor mechanisms. These enzymes offer potential targets to treat neuropathic pain.
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Proteomic and metabolomic analysis of inhibition of Monoacylglycerol Lipase (MAGL) in human prostate cancer.
Journal of Clinical Oncology, 2010Co-Authors: Donald P. Lombardi, Daniel K Nomura, Benjamin F CravattAbstract:e15035 Background: In a screen of serine hydrolases, we previously identified Monoacylglycerol Lipase (MAGL) as a fatty acid metabolic enzyme that had a 4-fold increased expression in aggressive co...
Daniel K Nomura - One of the best experts on this subject based on the ideXlab platform.
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therapeutic potential of Monoacylglycerol Lipase inhibitors
Life Sciences, 2013Co-Authors: Melinda M Mulvihill, Daniel K NomuraAbstract:Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown beneficial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase Monoacylglycerol Lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases.
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Monoacylglycerol Lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer
Chemistry & Biology, 2011Co-Authors: Daniel K Nomura, Jonathan Z Long, Anna M. Ward, Donald P. Lombardi, Sherry Niessen, Jae Won Chang, Heather H Hoover, Benjamin F CravattAbstract:Summary Cancer cells couple heightened lipogenesis with lipolysis to produce fatty acid networks that support malignancy. Monoacylglycerol Lipase (MAGL) plays a principal role in this process by converting monoglycerides, including the endocannabinoid 2-arachidonoylglycerol (2-AG), to free fatty acids. Here, we show that MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and that pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. These effects were partially reversed by treatment with fatty acids or a cannabinoid receptor-1 (CB1) antagonist, and fully reversed by cotreatment with both agents. We further show that MAGL is part of a gene signature correlated with epithelial-to-mesenchymal transition and the stem-like properties of cancer cells, supporting a role for this enzyme in protumorigenic metabolism that, for prostate cancer, involves the dual control of endocannabinoid and fatty acid pathways.
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Chronic Monoacylglycerol Lipase blockade causes functional antagonism of the endocannabinoid system
Nature Neuroscience, 2010Co-Authors: Joel E Schlosburg, Peter T. Nguyen, Divya Ramesh, Lamont Booker, Jonathan Z Long, Daniel K Nomura, Steven G. Kinsey, Jacqueline L Blankman, James J. BurstonAbstract:Scholsburg and colleagues show that prolonged inactivation of Monoacylglycerol Lipase, the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol, antagonizes the brain endocannabinoid system. This is manifested as tolerance, impaired plasticity and receptor desensitization; these effects are similar to the effects of prolonged exposure to drugs of abuse.
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Proteomic and metabolomic analysis of inhibition of Monoacylglycerol Lipase (MAGL) in human prostate cancer.
Journal of Clinical Oncology, 2010Co-Authors: Donald P. Lombardi, Daniel K Nomura, Benjamin F CravattAbstract:e15035 Background: In a screen of serine hydrolases, we previously identified Monoacylglycerol Lipase (MAGL) as a fatty acid metabolic enzyme that had a 4-fold increased expression in aggressive co...
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Monoacylglycerol Lipase regulates a fatty acid network that promotes cancer pathogenesis
Cell, 2010Co-Authors: Daniel K Nomura, Jonathan Z Long, Sherry Niessen, Heather Hoover, Shuwing Ng, Benjamin F CravattAbstract:SUMMARY Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme Monoacylglycerol Lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in nonaggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity— phenotypes that are reversed by an MAGL inhibitor. Impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of protumorigenic signals.
Carlotta Granchi - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study
Molecules (Basel Switzerland), 2020Co-Authors: Vibhu Jha, Carlotta Granchi, Filippo Minutolo, Giulio Poli, Marco Macchia, Marzia Biagi, Valeria Spinelli, Miriana Di Stefano, Tiziano TuccinardiAbstract:Monoacylglycerol Lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson’s and Alzheimer’s disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors.
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An updated patent review of Monoacylglycerol Lipase (MAGL) inhibitors (2018-present).
Expert opinion on therapeutic patents, 2020Co-Authors: Giulia Bononi, Filippo Minutolo, Tiziano Tuccinardi, Flavio Rizzolio, Giulio Poli, Marco Macchia, Carlotta GranchiAbstract:Monoacylglycerol Lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradati...
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Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible Monoacylglycerol Lipase (MAGL) inhibitors
Journal of enzyme inhibition and medicinal chemistry, 2019Co-Authors: Giulio Poli, Isabella Caligiuri, Filippo Minutolo, Tiziano Tuccinardi, Flavio Rizzolio, Marco Macchia, Margherita Lapillo, Vibhu Jha, Nayla Mouawad, Carlotta GranchiAbstract:Monoacylglycerol Lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The ident...
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New diterpenes from Salvia pseudorosmarinus and their activity as inhibitors of Monoacylglycerol Lipase (MAGL).
Fitoterapia, 2018Co-Authors: Marinella De Leo, Carlotta Granchi, Giulio Poli, Conny Guillen Huallpa, Britt Alvarado, Nunziatina De Tommasi, Alessandra BracaAbstract:Abstract As a part of our ongoing research program on compounds from higher plants with lactate dehydrogenase (LDH) and Monoacylglycerol Lipase (MAGL) inhibitory activities, three new neoclerodane diterpene 12-deacetylsplendidin C (1), pseudorosmaricin (2), and 2-dehydroxysalvileucanthsin A (3) along with six known compounds were isolated from Salvia pseudorosmarinus aerial part extracts. Their structures were determined by spectroscopic and spectrometric techniques including 1D- and 2D NMR, and MS analyses. The isolated diterpenes were assayed for their inhibitory activity on LDH5 and MAGL, two enzymes covering key roles in the peculiar energetic metabolism of malignant tumours. All the assayed diterpenes showed negligible activity on LDH5, whereas the known jewenol A (4) displayed a moderate inhibition activity on MAGL, showing an IC50 value of 46.8μM and it proved to be a reversible MAGL inhibitor. Docking and molecular dynamic simulation studies where thus performed to evaluate the binding mode of 4 within MAGL.
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discovery of long chain salicylketoxime derivatives as Monoacylglycerol Lipase magl inhibitors
European Journal of Medicinal Chemistry, 2018Co-Authors: Giulia Bononi, Carlotta Granchi, Isabella Caligiuri, Giulio Poli, Margherita Lapillo, Massimiliano Giannotti, Daniela Nieri, Serena Fortunato, Maguie El Boustani, Kathryn E CarlsonAbstract:Monoacylglycerol Lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.
Daniele Piomelli - One of the best experts on this subject based on the ideXlab platform.
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Assay of Monoacylglycerol Lipase Activity.
Methods of Molecular Biology, 2016Co-Authors: Kwang-mook Jung, Daniele PiomelliAbstract:Monoacylglycerol Lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). 2-AG is one of the main endogenous lipid agonists for cannabinoid receptors in the brain and elsewhere in the body. In the central nervous system (CNS), MGL is localized to presynaptic nerve terminals of both excitatory and inhibitory synapses, where it helps control the regulatory actions of 2-AG on synaptic transmission and plasticity. In this chapter, we describe an in vitro method to assess MGL activity by liquid chromatography/mass spectrometry (LC/MS)-based quantitation of the reaction product. This method may be used to determine the basal or altered MGL activity in various cells or animal tissues after pharmacological, genetic, or biological manipulations. In addition, this assay can be used for MGL inhibitor screening using purified recombinant enzyme or MGL-overexpressing cells.
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Pretreatment with the Monoacylglycerol Lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic-ischemic brain injury in rats.
Pediatric research, 2012Co-Authors: Silvia Carloni, Daniele Piomelli, Daniel Alonso-alconada, Silvia Girelli, Andrea Duranti, Andrea Tontini, Enrique Hilario, Antonia Alvarez, Walter BalduiniAbstract:Pretreatment with the Monoacylglycerol Lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic–ischemic brain injury in rats
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discovery of potent and reversible Monoacylglycerol Lipase inhibitors
Chemistry & Biology, 2009Co-Authors: Alvin R King, Alessio Lodola, Daniele Piomelli, Kwang-mook Jung, Emmanuel Y Dotsey, Azar Ghomian, Yan Qiu, Marco MorAbstract:Monoacylglycerol Lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Previous efforts to design MGL inhibitors have focused on chemical scaffolds that irreversibly block the activity of this enzyme. Here, we describe two naturally occurring terpenoids, pristimerin and euphol, which inhibit MGL activity with high potency (median effective concentration, IC(50) = 93 nM and 315 nM, respectively) through a reversible mechanism. Mutational and modeling studies suggest that the two agents occupy a common hydrophobic pocket located within the putative lid domain of MGL, and each reversibly interacts with one of two adjacent cysteine residues (Cys(201) and Cys(208)) flanking such pocket. This previously unrecognized regulatory region might offer a molecular target for potent and reversible inhibitors of MGL.
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a critical cysteine residue in Monoacylglycerol Lipase is targeted by a new class of isothiazolinone based enzyme inhibitors
British Journal of Pharmacology, 2009Co-Authors: Alvin R King, Alessio Lodola, Caterina Carmi, Jin Fu, Daniele PiomelliAbstract:Background and purpose: Monoacylglycerol Lipase (MGL) is a presynaptic serine hydrolase that inactivates the endocannabinoid neurotransmitter, 2-arachidonoyl-sn-glycerol. Recent studies suggest that cysteine residues proximal to the enzyme active site are important for MGL function. In the present study, we characterize the role of cysteines in MGL function and identify a series of cysteine-reactive agents that inhibit MGL activity with nanomolar potencies by interacting with cysteine residue 208.
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A critical cysteine residue in Monoacylglycerol Lipase is targeted by a new class of isothiazolinone‐based enzyme inhibitors
British journal of pharmacology, 2009Co-Authors: Alvin R King, Alessio Lodola, Caterina Carmi, Marco Mor, Daniele PiomelliAbstract:Background and purpose: Monoacylglycerol Lipase (MGL) is a presynaptic serine hydrolase that inactivates the endocannabinoid neurotransmitter, 2-arachidonoyl-sn-glycerol. Recent studies suggest that cysteine residues proximal to the enzyme active site are important for MGL function. In the present study, we characterize the role of cysteines in MGL function and identify a series of cysteine-reactive agents that inhibit MGL activity with nanomolar potencies by interacting with cysteine residue 208.
Tiziano Tuccinardi - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study
Molecules (Basel Switzerland), 2020Co-Authors: Vibhu Jha, Carlotta Granchi, Filippo Minutolo, Giulio Poli, Marco Macchia, Marzia Biagi, Valeria Spinelli, Miriana Di Stefano, Tiziano TuccinardiAbstract:Monoacylglycerol Lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson’s and Alzheimer’s disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors.
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An updated patent review of Monoacylglycerol Lipase (MAGL) inhibitors (2018-present).
Expert opinion on therapeutic patents, 2020Co-Authors: Giulia Bononi, Filippo Minutolo, Tiziano Tuccinardi, Flavio Rizzolio, Giulio Poli, Marco Macchia, Carlotta GranchiAbstract:Monoacylglycerol Lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradati...
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Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible Monoacylglycerol Lipase (MAGL) inhibitors
Journal of enzyme inhibition and medicinal chemistry, 2019Co-Authors: Giulio Poli, Isabella Caligiuri, Filippo Minutolo, Tiziano Tuccinardi, Flavio Rizzolio, Marco Macchia, Margherita Lapillo, Vibhu Jha, Nayla Mouawad, Carlotta GranchiAbstract:Monoacylglycerol Lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The ident...
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A patent review of Monoacylglycerol Lipase (MAGL) inhibitors (2013-2017).
Expert Opinion on Therapeutic Patents, 2017Co-Authors: Carlotta Granchi, Isabella Caligiuri, Filippo Minutolo, Flavio Rizzolio, Tiziano TuccinardiAbstract:ABSTRACTIntroduction: Monoacylglycerol Lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid 2-arachidonoylglycerol. Because of this key role, selective ina...
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a patent review of Monoacylglycerol Lipase magl inhibitors 2013 2017
Expert Opinion on Therapeutic Patents, 2017Co-Authors: Carlotta Granchi, Isabella Caligiuri, Filippo Minutolo, Flavio Rizzolio, Tiziano TuccinardiAbstract:ABSTRACTIntroduction: Monoacylglycerol Lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid 2-arachidonoylglycerol. Because of this key role, selective inactivation of MAGL represents an interesting approach to obtain desirable effects in several diseases. Furthermore, MAGL is upregulated in cancer cells and primary tumors and its inhibition in aggressive breast, ovarian, and melanoma cancer cells impairs cell migration, invasiveness, and tumorigenicity.Areas covered: This review covers patent literature on MAGL inhibitors and their applications published from 2013 to 2017.Expert opinion: MAGL inhibition has gained considerable importance in many therapeutic fields and one compound has been subjected to Phase I studies. Even if a reasonable number of patents have been recently reported, novel MAGL inhibitors are still required, especially novel chemical classes displaying a reversible mechanism of action.