A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Ming Jiang, Mirjam Huizenga, Jonah L. Wirt, János Pálóczi, Avand Amedi, Richard J. B. H. N. van den Berg, J. Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter P. F. Driever, Bogdan I. Florea, Uwe Grether, Antonius P. A. Janssen, Thomas Hankemeier, Laura H. Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F. Stevens, Daan van der Vliet, Tom van der Wel, Matthias Wittwer, C. A. A. VAN BOECKEL, Pál Pacher, Andrea G. Hohmann, Mario van der Stelt
Abstract
Abstract Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl 4 -induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB 1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB 2 , but not CB 1 , antagonists. The CB 1 antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.