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BioAssay: AID 504619

Inhibitors of T-Type Calcium Channels (Cav3.2 HEK whole cell CRC)

T-type Ca2+ channels are also called low voltage-activated channels because they open at voltages near the resting membrane potential of most cells. In many types of neurons, Ca2+ influx through T-type channels triggers low-threshold spikes, which in turn trigger a burst of action potentials mediated by Na+ channels (1). Burst firing is thought to play an important role in the synchronized more ..
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 Tested Compounds
 Tested Compounds
All(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
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Active(1)
 
 
AID: 504619
Data Source: Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters (T type Cav3.2 HEK whole cell current (CRC))
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: NIH Molecular Libraries Screening Center Network
Deposit Date: 2011-03-30

Data Table ( Complete ):           Active    All
Target
Sequence: voltage-dependent T-type calcium channel subunit alpha-1H isoform a [Homo sapiens]
Description ..   

Gene:CACNA1H     Conserved Domain     Related Protein 3D Structures     More BioActivity Data..
BioActive Compound: 1
Depositor Specified Assays
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AIDNameTypeComment
463087Inhibitors of Cav3 T-type Calcium Channelssummary
449739Inhibitors of Cav3 T-type Calcium Channels: Primary Screenscreening
489005Inhibitors of T-Type Calcium Channelconfirmatory
493021Inhibitors of T-Type Calcium Channelsconfirmatory
493022Inhibitors of T-Type Calcium Channels (SynthLib1)confirmatory
493023Inhibitors of T-Type Calcium Channels (SynthLib2)confirmatory
493041Inhibitors of T-Type Calcium Channels (SynthLib3)confirmatory
504425Mode of action assay-Specificity dose response assay for the identification of selective inhibitors of T-type calcium subunit Cav3.2 in the Cav3.3 expressing cell line on automated patch clampconfirmatory
504426Mode of action assay-Dose response assay for compounds that inhibit T-type calcium channel subunit Cav3.2 on automated patch clampconfirmatory
504579Inhibitors of T-Type Calcium Channels (rat DRG neuron currents)otherTtype DRG neuron currents (rat)
504584Inhibitors of T-Type Calcium Channels (Ancillary Pharm)otherTtype (Ancillary Binding Assay)
Description:
Assay Provider: Xinmin Xie
Assay Provider Affiliation: Bioscience Division, SRI International, Menlo Park, CA
Grant Title: HTS Assay for Cav3 T-Type Channels using FLIPR
Grant Number: NS050771-01

T-type Ca2+ channels are also called low voltage-activated channels because they open at voltages near the resting membrane potential of most cells. In many types of neurons, Ca2+ influx through T-type channels triggers low-threshold spikes, which in turn trigger a burst of action potentials mediated by Na+ channels (1). Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, and also in a wider range of neurological disorders characterized by thalamocortical dysrhythmia (2). Prominent T-currents are also observed in dorsal root ganglion neurons, with subsets of nociceptors expressing more T-current than high voltage-activated Ca2+ currents (3). Considerable evidence supports the notion that a T-channel antagonist would be a useful drug for the treatment of pain and epilepsy (4).

1. Perez-Reyes, E: Molecular physiology of low-voltage-activated T-type calcium channels. Physiol. Rev. 2003; 83: 117-161.
2. Llinas, R R, Ribary, U, Jeanmonod, D, Kronberg, E, and Mitra, P P: Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 15222-15227.
3. Nelson, M T, Joksovic, P M, Perez-Reyes, E, and Todorovic, S M: The endogenous redox agent L-cysteine induces T-type Ca2+ channel-dependent sensitization of a novel subpopulation of rat peripheral nociceptors. J. Neurosci. 2005; 25: 8766-8775.
4. Nelson, M, Todorovic, S, and Perez-Reyes, E: The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des 2006; 12: 2189-2197.
Protocol
The purpose of this assay was to follow up on the confirmatory and dose-response testing of the lead SAR series to characterize the compound using whole cell voltage clamp assays in human Cav3.2 expressing HEK cells to determine effects on T-type Ca2+ currents. Concentration response curves were measured and aggregated from 2-5 experiments per concentration ranging from 3.3nM to 10uM and reported as inhibition (percent control current).
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1VUIDVanderbilt External substance identifierString
2Avg_percent_inhib_0.0033_uM (0.0033μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
3Stderr_Avg_percent_inhib_0.0033_uM (0.0033μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
4Avg_percent_inhib_0.010_uM (0.01μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
5Stderr_Avg_percent_inhib_0.010_uM (0.01μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
6Avg_percent_inhib_0.033_uM (0.033μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
7Stderr_Avg_percent_inhib_0.033_uM (0.033μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
8Avg_percent_inhib_0.100_uM (0.1μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
9Stderr_Avg_percent_inhib_0.100_uM (0.1μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
10Avg_percent_inhib_0.330_uM (0.33μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
11Stderr_Avg_percent_inhib_0.330_uM (0.33μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
12Avg_percent_inhib_1.0_uM (1μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
13Stderr_Avg_percent_inhib_1.0_uM (1μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
14Avg_percent_inhib_3.3_uM (3.3μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
15Stderr_Avg_percent_inhib_3.3_uM (3.3μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
16Avg_percent_inhib_10.0_uM (10μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
17Stderr_Avg_percent_inhib_10.0_uM (10μM**)Inhibition (% control current measurement) at stated concentration of ML218 in human Cav3.2 expressing HEK cellsFloat%
18Avg_IC50_uM*Average Inhibition concentration 50 (IC50) expressed in micromolar units of ML218 for T-type Ca2+ currents in human Cav3.2 expressing HEK cellsFloatμM

* Activity Concentration. ** Test Concentration.
Additional Information
Grant Number: NS050771-01

Data Table (Concise)
Classification
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