Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain
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- 作者：Margherita Brindisi ; Samuele Maramai ; Sandra Gemma ; Simone Brogi ; Alessandro Grillo ; Lorenzo Di Cesare Mannelli ; Emanuele Gabellieri ; Stefania Lamponi ; Simona Saponara ; Beatrice Gorelli ; Daniele Tedesco ; Tommaso Bonfiglio ; Christophe Landry ; Kwang-Mook Jung ; Andrea Armirotti ; Livio Luongo ; Alessia Ligresti ; Fabiana Piscitelli ; Carlo Bertucci ; Marie-Pierre Dehouck ; Giuseppe Campiani ; Sabatino Maione ; Carla Ghelardini ; Anna Pittaluga ; Daniele Piomelli ; Vincenzo Di Marzo ; Stefania Butini
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 24, 2016
- 年：2016
- 卷：59
- 期：6
- 页码：2612-2632
- 全文大小：1083K
- ISSN：1520-4804
文摘
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.