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Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

  • Author(s): 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
  • et al.

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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