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|Title:||Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain||Authors:||Brindisi, Margherita
Di Cesare Mannelli, Lorenzo
Jung, Kwang Mook
Dehouck, Marie Pierre
Di Marzo, Vincenzo
|Keywords:||Animals; Arachidonic Acids; Blood-Brain Barrier; Brain; Cell Membrane; Drug Design; Encephalomyelitis, Autoimmune, Experimental; Endocannabinoids; Glycerides; HEK293 Cells; Humans; Mice; Models, Molecular; Monoacylglycerol Lipases; Multiple Sclerosis; Mutagenicity Tests; Neuralgia; Organoplatinum Compounds; Pain; Permeability; Proteomics; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship||Issue Date:||2016||Project:||None||Journal:||JOURNAL OF MEDICINAL CHEMISTRY||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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