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

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 pe...

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Veröffentlicht in:Nature Communications 2023-12, Vol.14 (1)
Hauptverfasser: Jiang, M., Huizenga, M.C.W., Wirth, J.L., Paloczi, J., Amedi, A., Berg, R.J.B.H.N. van den, Benz, J., Collin, L., Deng, H., Di, X., Driver, W.F., Florea, B.I., Grether, U., Janssen, A.P.A., Hankemeier, T., Heitman, L.H., Lam, T.W., Mohr, F., Pavlovic, A., Ruf, I., Hurk, H. van den, Stevens, A.F., Vliet, D. van der, Wel, T. van der, Wittwer, M.B., Boeckel, C.A.A. van, Pacher, P., Hohmann, A.G., Stelt, M. van der
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Sprache:eng
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Zusammenfassung: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.
DOI:10.1038/s41467-023-43606-3