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BioAssay: AID 724036

Displacement of [3H]epibatidine from rat recombinant alpha3beta4 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis

In our search for selective agonists for the alpha(4)beta(2) subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding more ..
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 Tested Compounds
 Tested Compounds
All(10)
 
 
Active(9)
 
 
Unspecified(1)
 
 
 Tested Substances
 Tested Substances
All(10)
 
 
Active(9)
 
 
Unspecified(1)
 
 
AID: 724036
Data Source: ChEMBL (936602)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2013-11-07
Modify Date: 2014-05-26

Data Table ( Complete ):           Active    All
Targets
Sequence: RecName: Full=Neuronal acetylcholine receptor subunit alpha-3; Flags: Precursor
Description ..   
Protein Family: Neurotransmitter-gated ion-channel ligand binding domain
Comment ..   

Gene:CHRNA3     Related Protein 3D Structures     More BioActivity Data..


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BioActive Compounds: 9
Description:
Title: Synthesis, pharmacology, and biostructural characterization of novel alpha4beta2 nicotinic acetylcholine receptor agonists.

Abstract: In our search for selective agonists for the alpha(4)beta(2) subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of alpha(4)beta(2) over other nAChR subtypes, primarily due to impaired binding at beta(4) containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (alpha(4))(2)(beta(2))(3) and (alpha(4))(3)(beta(2))(2) receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both alpha(4)-beta(2) and alpha(4)-alpha(4) binding sites, while the close analogue N,N-dimethyl-4-(1,4-dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via alpha(4)-beta(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.
(PMID: 23256554)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment
Assay Type: Binding

Assay Data Source: Scientific Literature

BAO: Assay Format: cell-based format

Assay Cell Type: HEK293

Target Type: Target is a defined protein complex, consisting of multiple subunits

Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Ki*Ki PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6Ki activity commentKi activity commentString
7Ki standard flagKi standard flagInteger
8Ki qualifierKi qualifierString
9Ki published valueKi published valueFloat
10Ki standard valueKi standard valueFloatnM
11Ki data validityKi data validityString
12Ki binding domainsKi binding domainsString
13Ki activity commentKi activity commentString
14Ki standard flagKi standard flagInteger
15Ki qualifierKi qualifierString
16Ki published valueKi published valueFloatμM
17Ki standard valueKi standard valueFloatnM
18Ki data validityKi data validityString
19Ki binding domainsKi binding domainsString

* Activity Concentration.

Data Table (Concise)
Classification
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