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

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

  • J Med Chem. 2016 Mar 24;59(6):2612-32. doi: 10.1021/acs.jmedchem.5b01812.
Margherita Brindisi 1,  Samuele Maramai 1,  Sandra Gemma 1,  Simone Brogi 1,  Alessandro Grillo 1,  Lorenzo Di Cesare Mannelli 2,  Emanuele Gabellieri 1,  Stefania Lamponi 1,  Simona Saponara 3,  Beatrice Gorelli 3,  Daniele Tedesco 4,  Tommaso Bonfiglio 5,  Christophe Landry 6,  Kwang-Mook Jung 7,  Andrea Armirotti 8,  Livio Luongo 9,  Alessia Ligresti 10,  Fabiana Piscitelli 10,  Carlo Bertucci 4,  Marie-Pierre Dehouck 6,  Giuseppe Campiani 1,  Sabatino Maione 9,  Carla Ghelardini 2,  Anna Pittaluga 5 11,  Daniele Piomelli 7,  Vincenzo Di Marzo 10,  Stefania Butini 1
Affiliations

Affiliations

  • 1 European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
  • 2 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.
  • 3 Department of Life Sciences, University of Siena , via Aldo Moro 2, I-53100 Siena, Italy.
  • 4 Department of Pharmacy and Biotechnology Alma Mater Studiorum, University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
  • 5 Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova , Viale Cembrano 4, Genova, 16148, Italy.
  • 6 Laboratoire de la Barrière Hémato-Encéphalique (LBHE), University of Artois , EA 2465, F62300 Lens, France.
  • 7 Department of Anatomy and Neurobiology, University of California , Irvine, California 92617, United States.
  • 8 Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
  • 9 Endocannabinoid Research Group, Department of Experimental Medicine, Division of Pharmacology "L. Donatelli", Second University of Napoli , 80138 Napoli, Italy.
  • 10 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , 80078 Pozzuoli (Napoli), Italy.
  • 11 Center of Excellence for Biomedical Research, University of Genova , Viale Benedetto XV, 16132 Genova, Italy.
PMID: 26888301 DOI: 10.1021/acs.jmedchem.5b01812
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.

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