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

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 (11) , Carlo Bertucci (11) , Marie-Pierre Dehouck (6) , Giuseppe Campiani (1) , Sabatino Maione (9) , Carla Ghelardini (2) , Anna Pittaluga (5) , Daniele Piomelli (12) , Vincenzo Di Marzo (10) , Stefania Butini (1)

1 European Research Centre for Drug Discovery and Development, Banchi di Sotto 55 and Dipartimento Farmaco Chimico Tecnologico
2 UNIVERSITY OF FIRENZE - UNIVERSITY OF FIRENZE
3 UNISI - Università degli Studi di Siena = University of Siena
4 University of Bologna/Università di Bologna
5 University of Genova [Genova, Italy]
6 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
7 UC - University of California
8 IIT - Instituto Italiano di Tecnologia
9 Second University of Napoli
10 ENDOCANNABINOID RESEARCH GROUP - Endocannabinoid Research Group, Institute of Biomolecular Chemistry
11 Institute of Biomolecular Biology
12 Department of Pharmacology

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.

Keywords: Inhibitors; Peptides and proteins; Neurophysiology; Central nervous system

Domains: Life Sciences [q-bio]

Margherita Brindisi, Samuele Maramai, Sandra Gemma, Simone Brogi, Alessandro Grillo, et al.. Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain. Journal of Medicinal Chemistry, 2016, 59 (6), pp.2612-2632. ⟨10.1021/acs.jmedchem.5b01812⟩. ⟨hal-02510278⟩