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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 &, 2023. "A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43606-3
    DOI: 10.1038/s41467-023-43606-3
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    References listed on IDEAS

    as
    1. Susanne Prokop & Péter Ábrányi-Balogh & Benjámin Barti & Márton Vámosi & Miklós Zöldi & László Barna & Gabriella M. Urbán & András Dávid Tóth & Barna Dudok & Attila Egyed & Hui Deng & Gian Marco Leggi, 2021. "PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    2. Andrea G. Hohmann & Richard L. Suplita & Nathan M. Bolton & Mark H. Neely & Darren Fegley & Regina Mangieri & Jocelyn F. Krey & J. Michael Walker & Philip V. Holmes & Jonathon D. Crystal & Andrea Dura, 2005. "An endocannabinoid mechanism for stress-induced analgesia," Nature, Nature, vol. 435(7045), pages 1108-1112, June.
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