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BioAssay: AID 624494

HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: SAR in D2 Binding Assay

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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Active(1)
 
 
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Active(1)
 
 
AID: 624494
Data Source: NCGC (DOP2703)
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-08-17
Hold-until Date: 2013-08-14
Modify Date: 2013-08-14

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compound: 1
Related Experiments
Show more
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
624455HTS Assay for Allosteric Antagonists of the Human D2 Dopamine Receptor: Hit Validation in HTRFConfirmatorysame 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
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 leads in the D2 radioligand binding assay.

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

MLPCN Grant: NS0676421
Assay Submitter (PI): David Sibley
Protocol
Radioligand displacement assay will be done to determine if the lead compounds are allosteric or orthosteric in nature, for interaction with the D2 receptor. Compounds will be evaluated for their ability to displace binding of methylspiperone.
Comment
A Ki of <= 1 was considered "active" and an activity score of 90 was assigned. A Ki between > 1 was considered "inactive" and a score of 10 was assigned.
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1KiBinding constant in micro Molar unitsFloatμM
2Compound QCString
Additional Information
Grant Number: NS0676421

Data Table (Concise)
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