1. Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.
- Author
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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, and Butini, Stefania
- Subjects
Blood-Brain Barrier ,Brain ,Cell Membrane ,Animals ,Humans ,Mice ,Multiple Sclerosis ,Encephalomyelitis ,Autoimmune ,Experimental ,Pain ,Neuralgia ,Organoplatinum Compounds ,Monoacylglycerol Lipases ,Arachidonic Acids ,Glycerides ,Receptor ,Cannabinoid ,CB1 ,Receptor ,Cannabinoid ,CB2 ,Endocannabinoids ,Mutagenicity Tests ,Proteomics ,Structure-Activity Relationship ,Drug Design ,Permeability ,Models ,Molecular ,HEK293 Cells ,Oxaliplatin ,Medicinal & Biomolecular Chemistry ,Medicinal and Biomolecular Chemistry ,Pharmacology and Pharmaceutical Sciences ,Organic 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.
- Published
- 2016