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

• Published in: Journal of medicinal chemistry Vol. 59; no. 6; pp. 2612 - 2632
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.03.2016; Amer Chemical Soc
• Subjects: Animals; Arachidonic Acids - metabolism; Blood-Brain Barrier - metabolism; Brain - metabolism; Cell Membrane - metabolism; Chemistry, Medicinal; Drug Design; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Endocannabinoids - metabolism; Glycerides - metabolism; HEK293 Cells; Humans; Life Sciences; Life Sciences & Biomedicine; Mice; Models, Molecular; Monoacylglycerol Lipases - antagonists & inhibitors; Multiple Sclerosis - drug therapy; Mutagenicity Tests; Neuralgia - chemically induced; Neuralgia - drug therapy; Organoplatinum Compounds; Pain - drug therapy; Permeability; Pharmacology & Pharmacy; Proteomics; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB2 - agonists; Science & Technology; Structure-Activity Relationship; NERVOUS-SYSTEM; MONOACYLGLYCEROL LIPASE; ENDOCANNABINOIDS; IN-VIVO; ANIMAL-MODELS; HYDROLYSIS; OXALIPLATIN; INHIBITORS; RECEPTORS; SOLVATION; Peptides and proteins; Inhibitors; Central nervous system; Neurophysiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01812

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.