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BioAssay: AID 624455

HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Hit Validation in HTRF

Dopamine receptors (DARs) are involved in the etiology and/or therapy of a number of neuropsychiatric and endocrine disorders. For instance, all receptor-based antiparkinsonian drugs work via stimulating the D2 DAR subtype whereas all FDA-approved antipsychotic agents are antagonists of this receptor. Most drugs targeting the D2 DAR are problematic, however, either being less efficacious as more ..
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 Tested Compounds
 Tested Compounds
All(1266)
 
 
Active(50)
 
 
Inactive(1169)
 
 
Inconclusive(49)
 
 
 Tested Substances
 Tested Substances
All(1280)
 
 
Active(50)
 
 
Inactive(1180)
 
 
Inconclusive(50)
 
 
AID: 624455
Data Source: NCGC (DOP2402)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-08-03

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compounds: 50
Related Experiments
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AIDNameTypeComment
485359HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Antagonists SummarySummarydepositor-specified cross reference
485344HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Primary Screen for AntagonistsScreeningsame project related to Summary assay
485347HTS Assay for Positive Allosteric Modulators of the Human D2 Dopamine Receptor: Primary Screen for PotentiatorsScreeningsame project related to Summary assay
624453HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Hit Validation in primary assayConfirmatorysame project related to Summary assay
624459HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Hit Validation in Parental Cell LineConfirmatorysame project related to Summary assay
624461HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Hit Validation in Radioligand AssayOthersame project related to Summary assay
624494HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: SAR in D2 Binding AssayOthersame project related to Summary assay
624495HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: SAR in D2 Beta Arrestin AssayConfirmatorysame project related to Summary assay
624496HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: SAR in Primary Assay.Confirmatorysame project related to Summary assay
624500HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: SAR in D3 Beta Arrestin AssayConfirmatorysame project related to Summary assay
624502HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: SAR in D3 Binding AssayOthersame project related to Summary assay
Description:
Dopamine receptors (DARs) are involved in the etiology and/or therapy of a number of neuropsychiatric and endocrine disorders. For instance, all receptor-based antiparkinsonian drugs work via stimulating the D2 DAR subtype whereas all FDA-approved antipsychotic agents are antagonists of this receptor. Most drugs targeting the D2 DAR are problematic, however, either being less efficacious as desired or possessing limiting side effects, most of which are due to reactivity at other receptors. One approach towards improved receptor specificity is to identify allosteric ligands that bind to less conserved regions of the receptor and therefore have the potential to be much more selective. The goal of this project is to use high throughput screening approaches to identify and develop novel, highly selective small molecule allosteric modulators of the D2 DAR for use as in vitro and in vivo pharmacological tools and in proof-of-concept experiments in animal models of neuropsychiatric disease. There are three different types of allosteric modulators that we are seeking, two of which will stimulate or augment receptor signaling, allosteric agonists and potentiators, while the third, allosteric antagonists, will attenuate receptor signaling. The present primary screening assay measures compound antagonism after an EC80 addition of dopamine by tracking calcium flux in a force-coupled, inducible Hek293 Trex D2 cell line. This assay measures activity of the hits in the D1 HTRF assay.

NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]

MLPCN Grant: NS064831
Assay Submitter (PI): David Sibley
Protocol
Cells stably expressing the D1 dopamine receptor will be run in an HTRF assay and compounds will be examined for the ability to inhibit the D1 mediated response.
Comment
Compound Ranking:
1. Compounds are first classified as having full titration curves, partial modulation, partial curve (weaker actives), single point activity (at highest concentration only), or inactive. See data field "Curve Description". For this assay, apparent inhibitors are ranked higher than compounds that showed apparent activation.
2. For all inactive compounds, PUBCHEM_ACTIVITY_SCORE is 0. For all active compounds, a score range was given for each curve class type given above. Active compounds have PUBCHEM_ACTIVITY_SCORE between 40 and 100. Inconclusive compounds have PUBCHEM_ACTIVITY_SCORE between 1 and 39. Fit_LogAC50 was used for determining relative score and was scaled to each curve class' score range.
Categorized Comment - additional comments and annotations
From ChEMBL:
Assay Type: Functional
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1PhenotypeIndicates type of activity observed: inhibitor, activator, fluorescent, cytotoxic, inactive, or inconclusive.String
2Potency*Concentration at which compound exhibits half-maximal efficacy, AC50. Extrapolated AC50s also include the highest efficacy observed and the concentration of compound at which it was observed.FloatμM
3EfficacyMaximal efficacy of compound, reported as a percentage of control. These values are estimated based on fits of the Hill equation to the dose-response curves.Float%
4Analysis CommentAnnotation/notes on a particular compound's data or its analysis.String
5Activity_ScoreActivity score.Integer
6Curve_DescriptionA description of dose-response curve quality. A complete curve has two observed asymptotes; a partial curve may not have attained its second asymptote at the highest concentration tested. High efficacy curves exhibit efficacy greater than 80% of control. Partial efficacies are statistically significant, but below 80% of control.String
7Fit_LogAC50The logarithm of the AC50 from a fit of the data to the Hill equation (calculated based on Molar Units).Float
8Fit_HillSlopeThe Hill slope from a fit of the data to the Hill equation.Float
9Fit_R2R^2 fit value of the curve. Closer to 1.0 equates to better Hill equation fit.Float
10Fit_InfiniteActivityThe asymptotic efficacy from a fit of the data to the Hill equation.Float%
11Fit_ZeroActivityEfficacy at zero concentration of compound from a fit of the data to the Hill equation.Float%
12Fit_CurveClassNumerical encoding of curve description for the fitted Hill equation.Float
13Excluded_PointsWhich dose-response titration points were excluded from analysis based on outlier analysis. Each number represents whether a titration point was (1) or was not (0) excluded, for the titration series going from smallest to highest compound concentrations.String
14Max_ResponseMaximum activity observed for compound (usually at highest concentration tested).Float%
15Activity at 0.00295 uM (0.00295μM**)% Activity at given concentration.Float%
16Activity at 0.015 uM (0.0147μM**)% Activity at given concentration.Float%
17Activity at 0.074 uM (0.0737μM**)% Activity at given concentration.Float%
18Activity at 0.369 uM (0.369μM**)% Activity at given concentration.Float%
19Activity at 1.840 uM (1.84μM**)% Activity at given concentration.Float%
20Activity at 46.10 uM (46.1μM**)% Activity at given concentration.Float%
21Compound QCNCGC designation for data stage: 'qHTS', 'qHTS Verification', 'Secondary Profiling'String

* Activity Concentration. ** Test Concentration.
Additional Information
Grant Number: NS064831

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
Classification
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