2. Academic Validation
  3. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence

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

  • Nat Commun. 2023 Dec 5;14(1):8039. doi: 10.1038/s41467-023-43606-3.
Ming Jiang # 1,  Mirjam C W Huizenga # 1,  Jonah L Wirt # 2,  Janos Paloczi 3,  Avand Amedi 1,  Richard J B H N van den Berg 4,  Joerg Benz 5,  Ludovic Collin 5,  Hui Deng 1,  Xinyu Di 6,  Wouter F Driever 1,  Bogdan I Florea 4,  Uwe Grether 5,  Antonius P A Janssen 1,  Thomas Hankemeier 6,  Laura H Heitman 7,  Tsang-Wai Lam 8,  Florian Mohr 1,  Anto Pavlovic 5,  Iris Ruf 5,  Helma van den Hurk 8,  Anna F Stevens 1,  Daan van der Vliet 1,  Tom van der Wel 1,  Matthias B Wittwer 5,  Constant A A van Boeckel 1,  Pal Pacher 3,  Andrea G Hohmann 9,  Mario van der Stelt 10
Affiliations

Affiliations

  • 1 Department of Molecular Physiology, Leiden University & Oncode Institute, Leiden, Netherlands.
  • 2 Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
  • 3 Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/NIAAA, Rockville, MD, USA.
  • 4 Department of Bio-organic Synthesis, Leiden University, Leiden, Netherlands.
  • 5 Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • 6 Metabolomics and analytics center, Leiden University, Leiden, Netherlands.
  • 7 Division of Drug Discovery and Safety, Leiden University & Oncode Institute, Leiden, Netherlands.
  • 8 Pivot Park Screening Centre, Oss, Netherlands.
  • 9 Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA. hohmanna@indiana.edu.
  • 10 Department of Molecular Physiology, Leiden University & Oncode Institute, Leiden, Netherlands. m.van.der.stelt@chem.leidenuniv.nl.
  • # Contributed equally.
PMID: 38052772 DOI: 10.1038/s41467-023-43606-3
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.

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