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BioAssay: AID 2256

Summary of efforts to identify compounds that inhibit transient receptor potential cation channel C4 (TRPC4)

Assay Implementation: Meng Wu Ph.D., Melissa Miller, Amy Scott M.S., Shunyou Long M.S., Kaiping Xu M.S., Bill Shi Ph.D., David Meyers Ph.D., Jia Xu Ph.D. ..more
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 Tested Compounds
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Probe(2)
 
 
Active(2)
 
 
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Probe(3)
 
 
Active(3)
 
 
AID: 2256
Data Source: Johns Hopkins Ion Channel Center (JHICC_TRPC4_Inh_Summary)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-01-15
Modify Date: 2013-03-27

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: alternatively spliced Trp4 [Mus musculus]
Description ..   
Protein Family: Transient receptor ion channel II

Gene:TRPC4     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: Chemical Probe: 2    Active: 2
Related Experiments
Show more
AIDNameTypeComment
2247Primary cell-based screen for identification of compounds that inhibit transient receptor potential cation channel C4 (TRPC4).Screeningdepositor-specified cross reference: Primary HTS assay for 304007 compounds, among them 1189 are active.
2636Confirmatory screen for identification of compounds that inhibit transient receptor potential cation channel C4 (TRPC4)Screeningdepositor-specified cross reference: Confirmatory screen of TRPC4 inhibitors with 2267 compounds tested in duplicates at the concentratio
2637Second confirmatory screen for identification of compounds that inhibit transient receptor potential cation channel C4 (TRPC4)Screeningdepositor-specified cross reference: Confirmatory screen of TRPC4 inhibitors with 2267 compounds tested in duplicates at the concentratio
434942Confirmation dose response assay for compounds that inhibit transient receptor potential cation channel C4 (TRPC4)Confirmatorydepositor-specified cross reference: Dose response assay for TRPC4 inhibitors with 2267 compounds, and 753 are active.
434948Specificity screen against TRPC6 for compounds that inhibit transient receptor potential cation channel C4 (TRPC4)Screeningdepositor-specified cross reference: Counter screen assay against TRPC6 for TRPC4 inhibitors with 2267 compounds tested, and 108 of them
434978Second counter screen for compounds that inhibit transient receptor potential cation channel C4 (TRPC4)Screeningdepositor-specified cross reference: Counter screen assay using the serotonin receptor 5HT1a in place of the mu-Opioid receptor for TRPC4
492981SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4) in TRPC6 expressing cells: MPD AssayScreeningdepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
492983SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4): Manual ElectrophysiologyOtherdepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
492987SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4) in TRPC6 expressing cells: MPD Assay CRCConfirmatorydepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
492988SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4): Primary HTS assayScreeningdepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
492991SAR Analysis for the identification of selective inhibits of the transient receptor potential cation channel C4 (TRPC4): Automated ElectrophysiologyConfirmatorydepositor-specified cross reference: SAR Analysis for the identification of selective inhibits of the transient receptor potential cation
492994SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4): Primary HTS assay CRCConfirmatorydepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
492995SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4): TRPC4 Serotonin Receptor CRC MPD assayConfirmatorydepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
492996SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C4 (TRPC4): ACh assay CRCConfirmatorydepositor-specified cross reference: SAR Analysis for the identification of selective inhibitors of the transient receptor potential cati
504554SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C6 (TRPC6) in cells expressing TRPC4: C4 assay CRCConfirmatorydepositor-specified cross reference
504589SAR Analysis for the identification of selective inhibits of the transient receptor potential cation channel C4 (TRPC4): Automated Electrophysiology_2Confirmatorydepositor-specified cross reference: SAR Analysis for the identification of selective inhibits of the transient receptor potential cation
504866SAR Analysis for the identification of selective inhibitors of the transient receptor potential cation channel C6 (TRPC6) in cells expressing TRPC4: C4 assay CRC 2Confirmatorydepositor-specified cross reference
Description:
Source (MLPCN Center Name): Johns Hopkins Ion Channel Center (JHICC)
Center Affiliation: Johns Hopkins University, School of Medicine
Screening Center PI: Min Li, Ph.D.
Assay Provider: Michael Zhu, Ph.D., Ohio State University
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R21 NS056942-01
Grant Proposal PI: Michael Zhu, Ph.D., Ohio State University
Assay Implementation: Meng Wu Ph.D., Melissa Miller, Amy Scott M.S., Shunyou Long M.S., Kaiping Xu M.S., Bill Shi Ph.D., David Meyers Ph.D., Jia Xu Ph.D.

Name: Primary cell-based screen for identification of compounds that inhibit transient receptor potential cation channel C4 (TRPC4).

Description:

Transient receptor potential (TRP) channels act as key regulators of many sensory systems including those for thermo-, photo-, and osmosensation [1-3]. A diversity of biological disorders has been linked to TRP channel malfunction ranging from neuropathic pain [4], cardiovascular diseases [5], to other diseases involving sensory physiology [6,7].

The TRP family of cation channels can be separated into seven subtypes according to structural similarity. Members of this family are nonselective cation channels that allow entry of extracellular calcium into cells resulting in a depolarization of membrane potential [8]. The mammalian TRPC (canonical) subfamily is proposed to function as store and second-messenger operated cation channels [9]. Disruption of TRPC may cause aberrant modulation of intracellular calcium and changes in membrane potential leading to activation of transcription factors, apoptosis, vascular contractility, platelet activation, and cardiac hypertrophy. Currently there are few pharmacological modulators of the TRPC family and no compounds known to target specific TRPC isoforms [10].

This assay summarizes the efforts in identification of test compounds
that inhibit transient receptor potential cation channel C4 (TRPC4). It is still ongoing at JHICC.

References:
1. Venkatachalam, K., and Montell, C. TRP Channels. Annual Review of Biochemistry 76(1), 387-417 (2007) PMID: 17579562
2. Clapham, D., Julius, D., Montell, C. and Schultz, G. International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacological Reviews 57(4), 427-450 (2005) PMID: 16382100
3. Reaves, B. J., and Wolstenholme, A. J. The TRP channel superfamily: insights into how structure, protein-lipid interactions and localization influence function. Biochemical Society Transactions 035(1), 77-80 (2007) PMID: 17233605
4. Patapoutian, A., Tate, S., and Woolf, C. J. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8(1), 55-68 (2009) PMID: 19116627
5. Vassort G, Alvarez J. Transient receptor potential: a large family of new channels of which several are involved in cardiac arrhythmia. Can J Physiol Pharmacol. 2009 Feb;87(2):100-7.PMID: 19234573
6. Nilius, B. TRP channels in disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1772(8), 805-812 (2007) PMID: 17368864
7. Woudenberg-Vrenken, T. E., Bindels, R. J. M., and Hoenderop, J. G. J. The role of transient receptor potential channels in kidney disease. Nat Rev Nephrol 5(8), 441-449 (2009) PMID: 19546862
8. Zhu, X., Jiang, M., Peyton, M., et al. trp, a Novel Mammalian Gene Family Essential for Agonist-Activated Capacitative Ca2+ Entry. Cell 85(5), 661-671 (1996) PMID: 8646775
9. Abramowitz, J., and Birnbaumer, L. Physiology and pathophysiology of canonical transient receptor potential channels. FASEB J. 23(2), 297-328 (2009) PMID: 18940894
10. Okuhara, D. Y., Hsia, A. Y., and Xie, M. Transient receptor potential channels as drug targets. Expert Opinion on Therapeutic Targets 11(3), 391-401 (2007) PMID: 17298296
Protocol
Please see the related bioassay (AID: 2247) for details of the protocol.
Comment
Result of this screening campaign has yielded a probe compound, ML204.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML204
PubChem Substance ID (SID) for probe 1: 97362164
PubChem Compound ID (CID) for probe 1: 230710
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 960 +/- 260
Target for probe 1: TRPC4 inhibitor _?OR activation (gi: 2935630)
Anti-target for probe 1: TRPC6 inhibitor_Ach activation
Fold selectivity for probe 1: 19
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK65430/ (ID: 2642530)
Grant number for probe 1: NS056942-01
PubMed Publication ID (PMID) for probe 1: 21795696
NCBI Book chapter title for probe 1: Novel Chemical Inhibitor of TRPC4 Channels
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML#Molecular library probe numberString
Additional Information
Grant Number: 1 R21 NS056942-01

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