A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38052772.
- Also identified by DOI 10.1038/s41467-023-43606-3 and PMC identifier 10698032.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>4</sub>-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB<sub>1</sub> activation. Antinociceptive efficacy of LEI-515 was blocked by CB<sub>2</sub>, but not CB<sub>1</sub>, antagonists. The CB<sub>1</sub> 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.
Medical subject headings
- Monoacylglycerol Lipases
- Monoglycerides