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

Nat Commun. 2023 Dec 5;14(1):8039. doi: 10.1038/s41467-023-43606-3.

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 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.

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Endocannabinoids
  • Mice
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases*
  • Monoglycerides*
  • Receptor, Cannabinoid, CB1
  • Rimonabant

Substances

  • Monoacylglycerol Lipases
  • Monoglycerides
  • Rimonabant
  • Endocannabinoids
  • Analgesics
  • Receptor, Cannabinoid, CB1