Bookmark and Share
BioAssay: AID 504420

Summary of the probe development efforts to identify inhibitors of human diacylglycerol lipase, beta (DAGLB)

Name: Summary of the probe development efforts to identify inhibitors of human diacylglycerol lipase, beta (DAGLB). ..more
_
   
 Tested Compounds
 Tested Compounds
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
 Tested Substances
 Tested Substances
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
AID: 504420
Data Source: The Scripps Research Institute Molecular Screening Center (DAGLB_INH_ SUMMARY)
BioAssay Type: Panel, Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2011-03-07
Modify Date: 2012-10-29

Data Table ( Complete ):           View Probe Data    View Active Data    View All Data
Target
BioActive Compounds: Chemical Probe: 3    Active: 3
Related Experiments
Show more
AIDNameTypeComment
504411Fluorescence-based primary biochemical high throughput screening assay to identify inhibitors of human diacylglycerol lipase, beta (DAGLB)Screeningdepositor-specified cross reference: Primary screen (DAGLB inhibitors in singlicate)
504445Fluorescence-based biochemical high throughput confirmation assay for inhibitors of human diacylglycerol lipase, beta (DAGLB)Screeningdepositor-specified cross reference: Confirmation screen (DAGLB inhibitors in triplicate)
602299Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of overexpressed DAGLb in vitro set 2Otherdepositor-specified cross reference: Late stage assay (overexpressed DAGLb inhibitors in vitro)
602300Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of overexpressed DAGLb in vitro set 3Otherdepositor-specified cross reference: Late stage assay (overexpressed DAGLb inhibitors in vitro)
602301Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of recombinant anti-target ABHD11 in vitro set 1Otherdepositor-specified cross reference: Late stage assay (ABHD11 inhibitors)
602302Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of overexpressed DAGLb in vitro set 1Otherdepositor-specified cross reference: Late stage assay (overexpressed DAGLb inhibitors in vitro)
602303Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of overexpressed DAGLb in vitro; triazole urea libraryOtherdepositor-specified cross reference: Late stage assay (overexpressed DAGLb inhibitors in vitro; triazole urea library)
602311Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of serine hydrolases in mouse brain membrane in vitro set 1Otherdepositor-specified cross reference: Late stage assay (serine hydrolases in mouse brain membrane inhibitors in vitro)
602312Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of recombinant anti-target ABHD11 in vitro set 2Otherdepositor-specified cross reference: Late stage assay (ABHD11 inhibitors in vitro)
602319Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of antitarget ABHD6 in vitroOtherdepositor-specified cross reference: Late stage assay (ABHD6 inhibitors in vitro)
602320Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based dose-response biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of DAGLb in vitroConfirmatorydepositor-specified cross reference: Late stage assay (DAGLb inhibitors in vitro in triplicate)
602321Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of serine hydrolases in mouse brain membrane in vitro set 3Otherdepositor-specified cross reference: Late stage assay (serine hydrolases in mouse brain membrane inhibitors in vitro)
602322Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based dose-response biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of antitarget ABHD6 in vitroConfirmatorydepositor-specified cross reference: Late stage assay (ABHD6 inhibitors in vitro in triplicate)
602323Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of serine hydrolases in mouse brain membrane in vitro set 2Otherdepositor-specified cross reference: Late stage assay (serine hydrolases in mouse brain membrane inhibitors in vitro)
602335Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based dose-response biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of anti-target ABHD6 in situConfirmatorydepositor-specified cross reference: Late stage assay (ABHD6 inhibitors in situ in triplicate)
602337Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): absorbance-based cell-based dose response assay to determine cytotoxicity of inhibitor compoundsConfirmatorydepositor-specified cross reference: Late stage dose response assay (cytotoxicity in five replicates)
602339Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): LCMS-based cell-based Activity-Based Protein Profiling (ABPP) SILAC selectivity analysisOtherdepositor-specified cross reference: Late stage assay (DAGLb SILAC selectivity analysis)
602341Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): LCMS-based cell-based Activity-Based Protein Profiling (ABPP) SILAC selectivity analysis for ABHD6Otherdepositor-specified cross reference: Late stage assay (ABHD6 SILAC selectivity analysis)
602343Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of mouse brain ABHD6 in vivo, set 2Otherdepositor-specified cross reference: Late stage assay (mouse brain ABHD6 inhibitors in vivo)
602345Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of mouse macrophage DAGLb in vivoOtherdepositor-specified cross reference: Late stage assay (mouse macrophage DAGLb inhibitors in vivo in duplicate)
602347Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of mouse brain ABHD6 in vivoOtherdepositor-specified cross reference: Late stage assay (mouse brain ABHD6 inhibitors in vivo in duplicate)
602349Late stage assay provider results from the probe development effort to identify inhibitors of DAGLb: fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) assay to distinguish systemic and peripheral inhibitorsOtherdepositor-specified cross reference: Late stage assay (distinguish systemic and peripheral inhibitors in duplicate)
602351Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): LCMS-based animal-based Activity-Based Protein Profiling (ABPP) MudPIT selectivity analysis for ABHD6Otherdepositor-specified cross reference: Late stage assay (ABHD6 MudPIT selectivity analysis in triplicate)
602353Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): LCMS-based animal-based Activity-Based Protein Profiling (ABPP) MudPIT selectivity analysisOtherdepositor-specified cross reference: Late stage assay (DAGLb MudPIT selectivity analysis in triplicate)
602354Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical dose-response gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of DAGLb in situConfirmatorydepositor-specified cross reference: Late stage dose-response (DAGLb inhibitors in situ in triplicate)
602355Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of serine hydrolases in vitroOtherdepositor-specified cross reference: Late stage assay (serine hydrolases inhibitors in vitro)
602403Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of recombinant antitarget DAGLa in vitroOtherdepositor-specified cross reference: Late stage assay (recombinant DAGLa inhibitors in vitro)
602415Assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): LC/MS-based biochemical inhibition of overexpressed DAGLb substrate turnover in vitroOtherdepositor-specified cross reference: Late stage assay (DAGLb substrate turnover inhibitors in vitro)
624039Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based dose-response biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of antitarget ABHD6 in vitro, set 2Confirmatorydepositor-specified cross reference: Late stage assay (ABHD6 inhibitors in vitro)
624041Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of mouse liver ABHD6 in vivoOtherdepositor-specified cross reference: Late stage assay (mouse liver ABHD6 inhibitors in vivo)
624077Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of mouse liver ABHD6 in vivo upon oral compound administrationOtherdepositor-specified cross reference: Late stage assay (mouse liver ABHD6 inhibitors in vivo upon oral compound administration)
624468Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): LCMS-based biochemical dose response assayConfirmatorydepositor-specified cross reference: Late stage dose response (DAGLb inhibitors in duplicate)
624472Late stage assay provider results from the probe development effort to identify inhibitors of diacylglycerol lipase, beta (DAGLb): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition of DAGLb by enantiomers of KT116Otherdepositor-specified cross reference: Late stage assay (DAGLb inhibition by enantiomers of KT116)
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Benjamin Cravatt, The Scripps Research Institute (TSRI)
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R01 DA025285
Grant Proposal PI: Benjamin Cravatt, The Scripps Research Institute (TSRI)
External Assay ID: DAGLB_INH_ SUMMARY

Name: Summary of the probe development efforts to identify inhibitors of human diacylglycerol lipase, beta (DAGLB).

Description:

Endocannabinoids (ECs) represent a unique group of lipids that function as chemical messengers in the nervous system. To date, the two principle ECs identified in mammals are N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol (2-AG). They have been implicated in various physiological and pathological functions including appetite, pain, sensation, memory, and addiction (1). Unlike traditional neurotransmitters, which are stored in vesicles, ECs are synthesized and released on demand, and then rapidly degraded to terminate signaling. Thus, the metabolic pathways that govern EC turnover are critical in determining the magnitude and duration of neuronal signaling events (2). Endocannabinoid biosynthesis, in contrast to degradation, is poorly understood. Recently, two serine hydrolases, DAGL-a and -B, were cloned and found to selectively cleave sn-1 acyl chains from diacylglycerols (DAG) to generate 2-AG in vitro (3). Their function in the nervous system was validated in vivo by the generation of DAGL-a and -B knock-out mice (4, 5). However, it is still unclear to what extent DAGL-a/B catalytic activity contributes to 2-AG-mediated signaling. The development of potent and selective inhibitors would offer a means to perturb DAGL-a/B activity in a selective, reversible, and temporally-controlled manner. Given the non-selective nature of current DAGL-a/B inhibitors (6), specific chemical probes would serve as invaluable tools to delineate DAGL-a/B function in 2-AG signaling networks of the brain.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of inhibitors of human diacylglycerol lipase, beta (DAGLB). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Di Marzo, V. (2008) Targeting the endocannabinoid system: to enhance or reduce?, Nat Rev Drug Discov 7, 438-455.
2. Ahn, K., McKinney, M. K., and Cravatt, B. F. (2008) Enzymatic pathways that regulate endocannabinoid signaling in the nervous system, Chem Rev 108, 1687-1707.
3. Bisogno, T., Howell, F., Williams, G., Minassi, A., Cascio, M. G., Ligresti, A., Matias, I., Schiano-Moriello, A., Paul, P., Williams, E. J., Gangadharan, U., Hobbs, C., Di Marzo, V., and Doherty, P. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain, J Cell Biol 163, 463-468.
4. Gao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., Shen, R., Zhang, M. Y., Strassle, B. W., Lu, P., Mark, L., Piesla, M. J., Deng, K., Kouranova, E. V., Ring, R. H., Whiteside, G. T., Bates, B., Walsh, F. S., Williams, G., Pangalos, M. N., Samad, T. A., and Doherty, P. (2010) Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice, J Neurosci 30, 2017-2024.
5. Tanimura, A., Yamazaki, M., Hashimotodani, Y., Uchigashima, M., Kawata, S., Abe, M., Kita, Y., Hashimoto, K., Shimizu, T., Watanabe, M., Sakimura, K., and Kano, M. (2010) The Endocannabinoid 2-Arachidonoylglycerol Produced by Diacylglycerol Lipase +/- Mediates Retrograde Suppression of Synaptic Transmission, Neuron 65, 320-327.
6. Hoover, H. S., Blankman, J. L., Niessen, S., and Cravatt, B. F. (2008) Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling, Bioorganic & Medicinal Chemistry Letters 18, 5838-5841.

Keywords:

Summary, Summary AID, Diacylglycerol lipase, Diacylglycerol lipase-beta, DAGL, DAGL-b, DAGL-beta, DAGLB, DAGL-B, hydrolase, serine hydrolase, appetite, pain, sensation, memory, addiction, fluorescence, HEK293T, membrane, lysate, EnzChek, fluorogenic lipase substrate, inhibitor, confirmation, triplicate, uHTS, HTS, 1536, high throughput screen, Scripps, Scripps Florida, Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Panel Information
Assays
    Data Table(Active)    Data Table(All)Show more
PID§NameSubstancePanel TargetsDescriptionAdditional Information
ActiveInactive
1AID 602322_1monoacylglycerol lipase ABHD6 [Mus musculus] [gi:31560264]
Taxonomy id: 10090
Gene id: 66082
2AID 602322_2sn1-specific diacylglycerol lipase beta [Mus musculus] [gi:31559956]
Taxonomy id: 10090
Gene id: 231871
3AID 602335_1monoacylglycerol lipase ABHD6 [Mus musculus] [gi:31560264]
Taxonomy id: 10090
Gene id: 66082
4AID 602335_2sn1-specific diacylglycerol lipase beta [Mus musculus] [gi:31559956]
Taxonomy id: 10090
Gene id: 231871
5AID 602337_1
6AID 602337_2
7AID 602320sn1-specific diacylglycerol lipase beta [Mus musculus] [gi:31559956]
Taxonomy id: 10090
Gene id: 231871
8AID 602354_1sn1-specific diacylglycerol lipase beta [Mus musculus] [gi:31559956]
Taxonomy id: 10090
Gene id: 231871
9AID 602354_2monoacylglycerol lipase ABHD6 [Mus musculus] [gi:31560264]
Taxonomy id: 10090
Gene id: 66082
10AID 624039sn1-specific diacylglycerol lipase beta [Mus musculus] [gi:31559956]
Taxonomy id: 10090
Gene id: 231871
11AID 624468sn1-specific diacylglycerol lipase beta [Mus musculus] [gi:31559956]
Taxonomy id: 10090
Gene id: 231871

§ Panel component ID.
Categorized Comment - additional comments and annotations
From PubChem:
Assay Cell Type: HEK 293T
From MLP Probe Report:
Probe count: 3
MLP Probe ML# for probe 1: ML296
PubChem Substance ID (SID) for probe 1: 125269096
PubChem Compound ID (CID) for probe 1: 53364510
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 0.8
Target for probe 1: ABHD6 (gi: 218931251)
Disease relevance for probe 1: Adiction
Anti-target for probe 1: DAGL-beta; 20+ SH targets
Fold selectivity for probe 1: >125; >1250
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK143552/ (ID: 3035868)
Grant number for probe 1: DA025285
MLP Probe ML# for probe 2: ML294
PubChem Substance ID (SID) for probe 2: 125269120
PubChem Compound ID (CID) for probe 2: 53364485
Probe type for probe 2: Inhibitor
IC50/EC50 (nM) for probe 2: 56
Target for probe 2: DAGL-beta (gi: 218931251)
Disease relevance for probe 2: Adiction
Anti-target for probe 2: ABHD6; 20+ SH targets; DAGL-alpha
Fold selectivity for probe 2: 0;>35;7
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK133443/ (ID: 3025428)
Grant number for probe 2: DA025285
MLP Probe ML# for probe 3: ML295
PubChem Substance ID (SID) for probe 3: 125269138
PubChem Compound ID (CID) for probe 3: 53364533
IC50/EC50 (nM) for probe 3: 38
Fold selectivity for probe 3: >85; >50
NCBI Book chapter link for probe 3: http://www.ncbi.nlm.nih.gov/books/NBK143552/ (ID: 3035868)
PubMed Publication ID (PMID) for probe 1: 23103940
PubMed Publication ID (PMID) for probe 2: 22690931,23103940
NCBI Book chapter title for probe 1: Optimization and characterization of triazole urea inhibitors for abhydrolase domain containing protein 6 (ABHD6)
NCBI Book chapter title for probe 2: Optimization and characterization of a triazole urea inhibitor for diacylglycerol lipase beta (DAGL-)
NCBI Book chapter title for probe 3: Optimization and characterization of triazole urea inhibitors for abhydrolase domain containing protein 6 (ABHD6)
Result Definitions
Show more
TIDNameDescriptionPID§Panel TargetsHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML #Unique alphanumeric identifier assigned to a chemical probe molecule within the Molecular Libraries Probe Production Centers Network (MLPCN).String
2IC50 [AID 602322_1]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.1monoacylglycerol lipase ABHD6 [Mus musculus]FloatμM
3Qualifier [AID 602322_2]Qualifier identifies if the resultant IC50 was determined manually to be less than or greater than its listed IC50.2sn1-specific diacylglycerol lipase beta [Mus musculus]String
4IC50 [AID 602322_2]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.2FloatμM
5IC50 [AID 602335_1]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.3monoacylglycerol lipase ABHD6 [Mus musculus]FloatμM
6Qualifier [AID 602335_2]Qualifier identifies if the resultant IC50 was determined manually to be less than or greater than its listed IC50.4sn1-specific diacylglycerol lipase beta [Mus musculus]String
7IC50 [AID 602335_2]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.4FloatμM
8Qualifier [AID 602337_1]Qualifier identifies if the resultant CC50 was determined manually to be greater than its listed CC50.5String
9CC50 [AID 602337_1]*The value for the concentration at which 50% of surviving cells are observed in serum-free medium; CC50 shown in micromolar.5FloatμM
10CC50 [AID 602337_2]*The value for the concentration at which 50% of surviving cells are observed in serum-containing medium; CC50 shown in micromolar.6FloatμM
11Average IC50 [AID 602320]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.7sn1-specific diacylglycerol lipase beta [Mus musculus]FloatμM
12Average IC50 [AID 602354_1]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.8sn1-specific diacylglycerol lipase beta [Mus musculus]FloatμM
13Average IC50 [AID 602354_2]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.9monoacylglycerol lipase ABHD6 [Mus musculus]FloatμM
14Average IC50 [AID 624039]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.10sn1-specific diacylglycerol lipase beta [Mus musculus]FloatμM
15Average IC50 [AID 624468]*The average concentration at which 50 percent of the activity in the antagonist assay is observed; (IC50) shown in micromolar.11sn1-specific diacylglycerol lipase beta [Mus musculus]FloatμM

* Activity Concentration. § Panel component ID.
Additional Information
Grant Number: 1 R01 DA025285

PageFrom: