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

Ming Jiang, Mirjam C. W. Huizenga, Jonah L. Wirt, Janos Paloczi, Avand Amedi, Richard J. B. H. N. Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter 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 Hurk, Anna F. Stevens, Daan Vliet, Tom Wel, Matthias B. Wittwer, Constant A. A. Boeckel, Pal Pacher, Andrea G. Hohmann () and Mario Stelt ()
Additional contact information
Ming Jiang: Leiden University & Oncode Institute
Mirjam C. W. Huizenga: Leiden University & Oncode Institute
Jonah L. Wirt: Indiana University
Janos Paloczi: National Institute of Health/NIAAA
Avand Amedi: Leiden University & Oncode Institute
Richard J. B. H. N. Berg: Leiden University
Joerg Benz: F. Hoffmann-La Roche Ltd.
Ludovic Collin: F. Hoffmann-La Roche Ltd.
Hui Deng: Leiden University & Oncode Institute
Xinyu Di: Leiden University
Wouter F. Driever: Leiden University & Oncode Institute
Bogdan I. Florea: Leiden University
Uwe Grether: F. Hoffmann-La Roche Ltd.
Antonius P. A. Janssen: Leiden University & Oncode Institute
Thomas Hankemeier: Leiden University
Laura H. Heitman: Leiden University & Oncode Institute
Tsang-Wai Lam: Pivot Park Screening Centre
Florian Mohr: Leiden University & Oncode Institute
Anto Pavlovic: F. Hoffmann-La Roche Ltd.
Iris Ruf: F. Hoffmann-La Roche Ltd.
Helma Hurk: Pivot Park Screening Centre
Anna F. Stevens: Leiden University & Oncode Institute
Daan Vliet: Leiden University & Oncode Institute
Tom Wel: Leiden University & Oncode Institute
Matthias B. Wittwer: F. Hoffmann-La Roche Ltd.
Constant A. A. Boeckel: Leiden University & Oncode Institute
Pal Pacher: National Institute of Health/NIAAA
Andrea G. Hohmann: Indiana University
Mario Stelt: Leiden University & Oncode Institute

Nature Communications, 2023, vol. 14, issue 1, 1-19

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 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.

Date: 2023
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DOI: 10.1038/s41467-023-43606-3

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