A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence

• Published in: Nature communications 2023-12, Vol.14 (1), p.8039-19, Article 8039
• Main 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, van den Hurk, Helma, Stevens, Anna F., van der Vliet, Daan, van der Wel, Tom, Wittwer, Matthias B., van Boeckel, Constant A. A., Pacher, Pal, Hohmann, Andrea G., van der Stelt, Mario
• Format: Article
• Language: English
• Subjects: 13; 2-Arachidonoylglycerol; 49/98; 631/154/309; 631/92/436; 64/60; 692/4017; 82/29; 82/47; 82/51; Analgesics; Analgesics - pharmacology; Animals; Antagonists; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; Carbon tetrachloride; Central nervous system; Chemotherapy; Effectiveness; Endocannabinoids; High-throughput screening; Humanities and Social Sciences; Inflammation; Inhibitors; Lipase; Liver; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Monoglycerides; multidisciplinary; Necrosis; Nervous system; Oxidative stress; Pain perception; Peripheral neuropathy; Receptor, Cannabinoid, CB1; Rimonabant; Science; Science (multidisciplinary); Side effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43606-3

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. 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.