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

AI Article Synopsis

  • * LEI-515 is a new MAGL inhibitor that only affects peripheral organs, increasing 2-AG levels without impacting the mouse brain, which could limit side effects.
  • * In animal studies, LEI-515 reduced liver damage and pain from chemotherapy without the negative effects seen with other MAGL inhibitors, suggesting it could be a safer option for treating inflammation and pain.

Article 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 CCl-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB activation. Antinociceptive efficacy of LEI-515 was blocked by CB, but not CB, antagonists. The CB 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698032PMC
http://dx.doi.org/10.1038/s41467-023-43606-3DOI Listing

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