A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence-Reference-Cited by-同舟云学术

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

Published:2023-12-05 Issue:1 Volume:14 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

Jiang Ming,Huizenga Mirjam C. W.^ORCID,Wirt Jonah L.^ORCID,Paloczi Janos^ORCID,Amedi Avand,van den Berg Richard J. B. H. N.,Benz Joerg,Collin Ludovic,Deng Hui,Di Xinyu,Driever Wouter F.^ORCID,Florea Bogdan I.,Grether Uwe^ORCID,Janssen Antonius P. A.^ORCID,Hankemeier Thomas,Heitman Laura H.^ORCID,Lam Tsang-Wai,Mohr Florian,Pavlovic Anto,Ruf Iris,van den Hurk Helma,Stevens Anna F.^ORCID,van der Vliet Daan^ORCID,van der Wel Tom^ORCID,Wittwer Matthias B.^ORCID,van Boeckel Constant A. A.,Pacher Pal^ORCID,Hohmann Andrea G.^ORCID,van der Stelt Mario^ORCID

Abstract

AbstractMonoacylglycerol 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.

Funder

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Link

https://www.nature.com/articles/s41467-023-43606-3.pdf

Reference60 articles.

1. Buckley, M. L. & Ramji, D. P. The influence of dysfunctional signaling and lipid homeostasis in mediating the inflammatory responses during atherosclerosis. Biochim. Biophys. Acta 1852, 1498–1510 (2015).

2. Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013).

3. Serhan, C. N., Chiang, N. & Van Dyke, T. E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8, 349–361 (2008).