Skip to main content
eScholarship
Open Access Publications from the University of California

UC Irvine

UC Irvine Previously Published Works bannerUC Irvine

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.
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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View