Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2023-12, Vol.14 (1), p.8039-8039, Article 8039

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 CCl 4 -induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB 1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB 2 , but not CB 1 , antagonists. The CB 1 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. Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.