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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 
Maramai, Samuele 
Gemma, Sandra 
Brogi, Simone
Grillo, Alessandro
Di Cesare Mannelli, Lorenzo
Gabellieri, Emanuele
Lamponi, Stefania 
Saponara, Simona
Gorelli, Beatrice
Tedesco, Daniele
Bonfiglio, Tommaso
Landry, Christophe
Jung, Kwang Mook
Armirotti, Andrea
Luongo, Livio
Ligresti, Alessia
Piscitelli, Fabiana
Bertucci, Carlo
Dehouck, Marie Pierre
Campiani, Giuseppe 
Maione, Sabatino
Ghelardini, Carla
Pittaluga, Anna
Piomelli, Daniele
Di Marzo, Vincenzo
Butini, Stefania 
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 
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.
ISSN: 0022-2623
DOI: 10.1021/acs.jmedchem.5b01812
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