2. Academic Validation
  3. Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression

Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression

  • Eur J Med Chem. 2024 Feb 26:268:116285. doi: 10.1016/j.ejmech.2024.116285.
Qingjing Hao 1,  Junwei Shi 1,  Zhilan Zhang 1,  Guoqing Yang 1,  Yunbao Zhi 1,  Ke Wang 1,  Dingchen Ma 1,  Shengnan Fu 1,  Haijuan Dong 2,  Zhuoer Zhi 1,  Wenting Zhang 1,  Tingting Li 3,  Jinxin Wang 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 The Public Laboratory Platform, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 38428273 DOI: 10.1016/j.ejmech.2024.116285
Abstract

Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol Lipase (MAGL), an essential Enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure-activity relationships (SAR) studies were discussed. Compound 27 (IC50 = 10.3 nM) exhibited high bioavailability (92.7%) and 2-AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress-induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.

Keywords

2-Arachidonoylglycerol; Depression; Monoacylglycerol lipase inhibitors; Piperazine-1-carbonyl quinolin-2(1H)-One derivatives; Rapid antidepressant effects.

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