IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-43606-3.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43606-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-43606-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yun-Feng Zhang & Jialiang Wu & Yingqi Wang & Natalie L. Johnson & Janardhan P. Bhattarai & Guanqing Li & Wenqiang Wang & Camilo Guevara & Hannah Shoenhard & Marc V. Fuccillo & Daniel W. Wesson & Mingh, 2023. "Ventral striatal islands of Calleja neurons bidirectionally mediate depression-like behaviors in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Stamatis Mourtakos & Georgia Vassiliou & Konstantinos Kontoangelos & Anastassios Philippou & Elias Tzavellas & José Francisco Tornero-Aguilera & Vicente Javier Clemente-Suárez & Charalabos Papageorgio, 2021. "Endocannabinoids and Heart Rate Variability Alterations after Exposure to Prolonged Intensive Physical Exercise of the Hellenic Navy SEALs," IJERPH, MDPI, vol. 19(1), pages 1-10, December.
    3. Aske L. Ejdrup & Matthew D. Lycas & Niels Lorenzen & Ainoa Konomi & Freja Herborg & Kenneth L. Madsen & Ulrik Gether, 2022. "A density-based enrichment measure for assessing colocalization in single-molecule localization microscopy data," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43606-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.