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- Title
A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.
- Authors
Jiang, Ming; Huizenga, Mirjam C. W.; Wirt, Jonah L.; Paloczi, Janos; Amedi, Avand; van den Berg, Richard J. B. H. N.; Benz, Joerg; Collin, Ludovic; Deng, Hui; Di, Xinyu; Driever, Wouter F.; Florea, Bogdan I.; Grether, Uwe; Janssen, Antonius P. A.; Hankemeier, Thomas; Heitman, Laura H.; Lam, Tsang-Wai; Mohr, Florian; Pavlovic, Anto; Ruf, Iris
- 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 CCl4-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB2, but not CB1, antagonists. The CB1 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.Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43606-3