Margherita Brindisi, Samuele Maramai, Sandra Gemma, Simone Brogi, Alessandro Grillo, Lorenzo Di Cesare Mannelli, Emanuele Gabellieri, Stefania Lamponi, Simona Saponara, Beatrice Gorelli, Daniele Tedesco, Tommaso Bonfiglio, Christophe Landry, Kwang-Mook Jung, Andrea Armirotti, Livio Luongo, Alessia Ligresti, Fabiana Piscitelli, Carlo Bertucci, Marie-Pierre Dehouck, Giuseppe Campiani, Sabatino Maione, Carla Ghelardini, Anna Pittaluga, Daniele Piomelli, Vincenzo Di Marzo, Stefania Butini
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...
March 24, 2016: Journal of Medicinal Chemistry