ArticleJournal of the American Chemical Society2015
Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 63 citations in OpenAlex.
- Chemical Probes for Investigating the Endocannabinoid System.Current topics in behavioral neurosciences · 2026Review
- The Pharmacological Profile of Plant-Derived Cannabinoids In Vitro.Current topics in behavioral neurosciences · 2026Review
- Site-Specific Competitive Kinase Inhibitor Target Profiling Using Phosphonate Affinity Tags.Molecular & cellular proteomics : MCP · 2025Article
- Lipid Alterations in Chronic Nonspecific Low Back Pain in the Chinese Population: A Metabolomic and Lipidomic Study.Bioengineering (Basel, Switzerland) · 2024Article
- Pharmacological Characterization of the Endocannabinoid Sensor GRABCannabis and cannabinoid research · 2024Article
- P2XBritish journal of pharmacology · 2024Article
- Structure-Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors.Journal of medicinal chemistry · 2024Article
- Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.Pharmacological reviews · 2023Review
- Technologies for Direct Detection of Covalent Protein-Drug Adducts.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Inhibition of diacylglycerol lipase β modulates lipid and endocannabinoid levels in theFrontiers in endocrinology · 2023Article
- Chemical Probes to Control and Visualize Lipid Metabolism in the Brain.Accounts of chemical research · 2022Review
- PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells.Nature communications · 2021Article
- Olaparib-Based Photoaffinity Probes for PARP-1 Detection in Living Cells.Chembiochem : a European journal of chemical biology · 2020Article
- Interactions Between Alcohol and the Endocannabinoid System.Alcoholism, clinical and experimental research · 2020Review
- DAGL-Beta Functions as a PUFA-Specific Triacylglycerol Lipase in Macrophages.Cell chemical biology · 2020Article
- Druggable Targets in Endocannabinoid Signaling.Advances in experimental medicine and biology · 2020Review
- ABHD2 Inhibitor Identified by Activity-Based Protein Profiling Reduces Acrosome Reaction.ACS chemical biology · 2019Article
- Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors.Journal of medicinal chemistry · 2019Article
- Activity-Based Protein Profiling Identifies α-Ketoamides as Inhibitors for Phospholipase A2 Group XVI.ACS chemical biology · 2019Article
- Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells.Journal of neuroinflammation · 2018Article
Corrections and comments
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Authors and funding
20 authors at 4 institutions in 2 countries.
Funding
Abstract
Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion, but they are currently lacking. Here, we describe the identification of a highly selective DAGL inhibitor using structure-guided and a chemoproteomics strategy to characterize the selectivity of the inhibitor in complex proteomes. Key to the success of this approach is the use of comparative and competitive activity-based proteome profiling (ABPP), in which broad-spectrum and tailor-made activity-based probes are combined to report on the inhibition of a protein family in its native environment. Competitive ABPP with broad-spectrum fluorophosphonate-based probes and specific β-lactone-based probes led to the discovery of α-ketoheterocycle LEI105 as a potent, highly selective, and reversible dual DAGL-α/DAGL-β inhibitor. LEI105 did not affect other enzymes involved in endocannabinoid metabolism including abhydrolase domain-containing protein 6, abhydrolase domain-containing protein 12, monoacylglycerol lipase, and fatty acid amide hydrolase and did not display affinity for the cannabinoid CB1 receptor. Targeted lipidomics revealed that LEI105 concentration-dependently reduced 2-AG levels, but not anandamide levels, in Neuro2A cells. We show that cannabinoid CB1-receptor-mediated short-term synaptic plasticity in a mouse hippocampal slice model can be reduced by LEI105. Thus, we have developed a highly selective DAGL inhibitor and provide new pharmacological evidence to support the hypothesis that "on demand biosynthesis" of 2-AG is responsible for retrograde signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.