| Title : A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence - Jiang_2023_Nat.Commun_14_8039 |
| Author(s) : Jiang M , Huizenga MCW , Wirt JL , Paloczi J , Amedi A , van den Berg R , Benz J , Collin L , Deng H , Di X , Driever WF , Florea BI , Grether U , Janssen APA , Hankemeier T , Heitman LH , Lam TW , Mohr F , Pavlovic A , Ruf I , van den Hurk H , Stevens AF , van der Vliet D , van der Wel T , Wittwer MB , van Boeckel CAA , Pacher P , Hohmann AG , van der Stelt M |
| Ref : Nat Commun , 14 :8039 , 2023 |
| 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(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. |
| ESTHER : Jiang_2023_Nat.Commun_14_8039 |
| PubMedSearch : Jiang_2023_Nat.Commun_14_8039 |
| PubMedID: 38052772 |
Jiang M, Huizenga MCW, Wirt JL, Paloczi J, Amedi A, van den Berg R, Benz J, Collin L, Deng H, Di X, Driever WF, Florea BI, Grether U, Janssen APA, Hankemeier T, Heitman LH, Lam TW, Mohr F, Pavlovic A, Ruf I, van den Hurk H, Stevens AF, van der Vliet D, van der Wel T, Wittwer MB, van Boeckel CAA, Pacher P, Hohmann AG, van der Stelt M (2023)
A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Nat Commun
14 :8039
Jiang M, Huizenga MCW, Wirt JL, Paloczi J, Amedi A, van den Berg R, Benz J, Collin L, Deng H, Di X, Driever WF, Florea BI, Grether U, Janssen APA, Hankemeier T, Heitman LH, Lam TW, Mohr F, Pavlovic A, Ruf I, van den Hurk H, Stevens AF, van der Vliet D, van der Wel T, Wittwer MB, van Boeckel CAA, Pacher P, Hohmann AG, van der Stelt M (2023)
Nat Commun
14 :8039