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J Med Chem. 2016 Mar 24;59(6):2612-32. doi: 10.1021/acs.jmedchem.5b01812. Epub 2016 Mar 7.

Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

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European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Firenze , V.le G. Pieraccini 6, 50139 Firenze, Italy.
Department of Life Sciences, University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
Department of Pharmacy and Biotechnology Alma Mater Studiorum, University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova , Viale Cembrano 4, Genova, 16148, Italy.
Laboratoire de la Barrière Hémato-Encéphalique (LBHE), University of Artois , EA 2465, F62300 Lens, France.
Department of Anatomy and Neurobiology, University of California , Irvine, California 92617, United States.
Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
Endocannabinoid Research Group, Department of Experimental Medicine, Division of Pharmacology "L. Donatelli", Second University of Napoli , 80138 Napoli, Italy.
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , 80078 Pozzuoli (Napoli), Italy.
Center of Excellence for Biomedical Research, University of Genova , Viale Benedetto XV, 16132 Genova, Italy.


We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.

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