title: 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.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Maramai
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Grillo
authors.affiliation: 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.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Gabellieri
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.affiliation: Department of Life Sciences, University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
authors.affiliation: Department of Life Sciences, University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gorelli
authors.affiliation: Department of Pharmacy and Biotechnology Alma Mater Studiorum, University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tedesco
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova , Viale Cembrano 4, Genova, 16148, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Bonfiglio
authors.affiliation: Laboratoire de la Barrière Hémato-Encéphalique (LBHE), University of Artois , EA 2465, F62300 Lens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Landry
authors.affiliation: Department of Anatomy and Neurobiology, University of California , Irvine, California 92617, United States.
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Endocannabinoid Research Group, Department of Experimental Medicine, Division of Pharmacology "L. Donatelli", Second University of Napoli , 80138 Napoli, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , 80078 Pozzuoli (Napoli), Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , 80078 Pozzuoli (Napoli), Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Department of Pharmacy and Biotechnology Alma Mater Studiorum, University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Bertucci
authors.affiliation: Laboratoire de la Barrière Hémato-Encéphalique (LBHE), University of Artois , EA 2465, F62300 Lens, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dehouck
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: Endocannabinoid Research Group, Department of Experimental Medicine, Division of Pharmacology "L. Donatelli", Second University of Napoli , 80138 Napoli, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: 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.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova , Viale Cembrano 4, Genova, 16148, Italy.|Center of Excellence for Biomedical Research, University of Genova , Viale Benedetto XV, 16132 Genova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
authors.affiliation: Department of Anatomy and Neurobiology, University of California , Irvine, California 92617, United States.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , 80078 Pozzuoli (Napoli), Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009152:Mutagenicity Tests; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010146:Pain / Q000188:drug therapy*; D010539:Permeability; D040901:Proteomics; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D009944:Organoplatinum Compounds; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000077150:Oxaliplatin; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases