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Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors
- Source :
- Journal of medicinal chemistry. 63(11)
- Publication Year :
- 2020
-
Abstract
- Most of the current monoacylglycerol lipase (MAGL) inhibitors function by an irreversible mechanism of action, causing a series of side effects. Herein, starting from irreversible inhibitors, 25 compounds were synthesized and evaluated in vitro for MAGL inhibition, among which, compound 36 showed the most potent inhibitory activity (IC50 = 15 nM). Crucially, docking studies demonstrated that the m-chlorine-substituted aniline fragment occupied a hydrophobic subpocket enclosed by side chains of Val191, Tyr194, Val270, and Lys273, which creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly ameliorated depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for depression.
- Subjects :
- Stereochemistry
Cell Survival
Drug Evaluation, Preclinical
Cell Line
chemistry.chemical_compound
Mice
Structure-Activity Relationship
Piperidines
In vivo
Drug Discovery
medicine
Structure–activity relationship
Animals
Humans
Enzyme Inhibitors
IC50
Binding Sites
In vitro
Monoacylglycerol Lipases
Protein Structure, Tertiary
Rats
Monoacylglycerol lipase
Molecular Docking Simulation
Kinetics
Mechanism of action
chemistry
Docking (molecular)
Drug Design
Microsomes, Liver
Molecular Medicine
Piperidine
medicine.symptom
Half-Life
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 63
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....5b5a9241f3ce2d8aca9e96b9ac2a9793