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Start Over Author "Janssen APA" Topic monoacylglycerol lipases
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1. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.

Author

Jiang M, Huizenga MCW, Wirt JL, Paloczi J, Amedi A, van den Berg RJBHN, 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, and van der Stelt M

Subjects
Animals, Mice, Rimonabant, Endocannabinoids, Analgesics pharmacology, Receptor, Cannabinoid, CB1, Mice, Inbred C57BL, Monoacylglycerol Lipases, Monoglycerides
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., (© 2023. The Author(s).)

Published
2023
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2. Design and Synthesis of Quenched Activity-based Probes for Diacylglycerol Lipase and α,β-Hydrolase Domain Containing Protein 6.

Author

van Rooden EJ, Kohsiek M, Kreekel R, van Esbroeck ACM, van den Nieuwendijk AMCH, Janssen APA, van den Berg RJBHN, Overkleeft HS, and van der Stelt M

Subjects
Aniline Compounds chemistry, Animals, Brain metabolism, Catalysis, Cell Line, Tumor, Copper chemistry, Cycloaddition Reaction, Fluorescent Dyes chemistry, Fluorescent Dyes metabolism, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring metabolism, Humans, Lipoprotein Lipase chemistry, Mice, Monoacylglycerol Lipases chemistry, Triazoles chemistry, Triazoles metabolism, Drug Design, Fluorescent Dyes chemical synthesis, Heterocyclic Compounds, 3-Ring chemical synthesis, Lipoprotein Lipase metabolism, Monoacylglycerol Lipases metabolism, Triazoles chemical synthesis
Abstract

Diacylglycerol lipases (DAGL) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. The fluorescent activity-based probes DH379 and HT-01 have been previously shown to label DAGLs and to cross-react with the serine hydrolase ABHD6. Here, we report the synthesis and characterization of two new quenched activity-based probes 1 and 2, the design of which was based on the structures of DH379 and HT-01, respectively. Probe 1 contains a BODIPY-FL and a 2,4-dinitroaniline moiety as a fluorophore-quencher pair, whereas probe 2 employs a Cy5-fluorophore and a cAB40-quencher. The fluorescence of both probes was quenched with relative quantum yields of 0.34 and 0.0081, respectively. The probes showed target inhibition as characterized in activity-based protein profiling assays using human cell- and mouse brain lysates, but were unfortunately not active in living cells, presumably due to limited cell permeability., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2018
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