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

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

SUBMITTER: Jiang M 

PROVIDER: S-EPMC10698032 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature