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BioAssay: AID 624421

qHTS of GLP-1 Receptor Inverse Agonists: Summary

The overall goal of this project was to develop a novel assay for discovering small molecule ligands for class B1 G protein-coupled receptors (GPCRs). Very few agonists (or inverse agonists) with generally weak activity for this entire group of physiologically important receptors are known to date. To establish proof-of-principle that this critical bottleneck can be overcome with a suitable screening approach, our studies focused on the class B1 receptor for glucagon-like peptide-1 (GLP-1R), a potential therapeutic target for diabetes and neurodegenerative disease. ..more
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AID: 624421
Data Source: NCGC (GLPIA1000)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-07-30
Target
Depositor Specified Assays
AIDNameTypeComment
624418qHTS of GLP-1 Receptor Inverse Agonists: Cytotox ScreenconfirmatoryCytotox qHTS AID
624417qHTS of GLP-1 Receptor Inverse Agonists (Inhibition Mode)confirmatoryqHTS AID
624152qHTS of GLP-1 Receptor Agonists: SummarysummarySummary AID for Agonists of GLP1
Description:
The overall goal of this project was to develop a novel assay for discovering small molecule ligands for class B1 G protein-coupled receptors (GPCRs). Very few agonists (or inverse agonists) with generally weak activity for this entire group of physiologically important receptors are known to date. To establish proof-of-principle that this critical bottleneck can be overcome with a suitable screening approach, our studies focused on the class B1 receptor for glucagon-like peptide-1 (GLP-1R), a potential therapeutic target for diabetes and neurodegenerative disease.

The assay was developed using a cell-based functional readout. Toward this goal, stably transfected HEK293 cell clones were established that co-express (i) a cAMP-responsive luciferase reporter gene, and (ii) constitutively active GLP-1R that upon ligand interaction inhibit (inverse agonists) the luciferase activity. In addition, two control cell lines were developed: (i) one that express only the cAMP-responsive reporter gene to enable initial exclusion of GLP-1R independent effects of candidate probes; and (ii) one with the reported gene cloned with another constitutively active orphan receptor GPR119 to enable exclusion of GLP-1R independent inhibitor effects of candidate inverse agonists.

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

Grant: NS064851
PI Name: Martin Beinborn, Tufts Medical Center
Protocol
Please see linked AIDs for detailed protocols for each respective assay.
Comment
This project is on-going and will be updated at a later point.
Additional Information
Grant Number: NS064851

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