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

Abstract : 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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https://hal-univ-artois.archives-ouvertes.fr/hal-02510278
Contributor : Virginie Justin-Labonne <>
Submitted on : Tuesday, March 17, 2020 - 4:08:33 PM
Last modification on : Wednesday, April 15, 2020 - 9:56:12 AM

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Margherita Brindisi, Samuele Maramai, Sandra Gemma, Simone Brogi, Alessandro Grillo, et al.. Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain. Journal of Medicinal Chemistry, American Chemical Society, 2016, 59 (6), pp.2612-2632. ⟨10.1021/acs.jmedchem.5b01812⟩. ⟨hal-02510278⟩

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