A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.
Ming JiangMirjam C W HuizengaJonah L WirtJanos PalocziAvand AmediRichard J B H N van den BergJoerg BenzLudovic CollinHui DengXinyu DiWouter F DrieverBogdan I FloreaUwe GretherAntonius P A JanssenThomas HankemeierLaura H HeitmanTsang-Wai LamFlorian MohrAnto PavlovicIris RufHelma van den HurkAnna F StevensDaan van der VlietTom van der WelMatthias B WittwerConstant A A van BoeckelPal PacherAndrea G HohmannMario van der SteltPublished in: Nature communications (2023)
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 4 -induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB 1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB 2 , but not CB 1 , antagonists. The CB 1 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.
Keyphrases
- liver injury
- chemotherapy induced
- oxidative stress
- anti inflammatory
- drug induced
- high fat diet induced
- quantum dots
- physical activity
- small molecule
- blood brain barrier
- neuropathic pain
- mental health
- wild type
- type diabetes
- spinal cord injury
- randomized controlled trial
- machine learning
- cancer therapy
- highly efficient
- spinal cord
- drug delivery
- cerebrospinal fluid
- newly diagnosed
- drug discovery
- risk assessment
- data analysis