학술논문
A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Document Type
article
Author
Ming Jiang; Mirjam C. W. Huizenga; Jonah L. Wirt; Janos Paloczi; Avand Amedi; Richard J. B. H. N. van den 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 van den Hurk; Anna F. Stevens; Daan van der Vliet; Tom van der Wel; Matthias B. Wittwer; Constant A. A. van Boeckel; Pal Pacher; Andrea G. Hohmann; Mario van der Stelt
Source
Nature Communications, Vol 14, Iss 1, Pp 1-19 (2023)
Subject
Language
English
ISSN
2041-1723
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.