Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptor AhR.
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F18%3A73586865" target="_blank" >RIV/61989592:15310/18:73586865 - isvavai.cz</a>
Result on the web
<a href="http://molpharm.aspetjournals.org/content/molpharm/early/2018/04/06/mol.118.112151.full.pdf" target="_blank" >http://molpharm.aspetjournals.org/content/molpharm/early/2018/04/06/mol.118.112151.full.pdf</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1124/mol.118.112151" target="_blank" >10.1124/mol.118.112151</a>
Alternative languages
Result language
angličtina
Original language name
Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptor AhR.
Original language description
Novel methyl-indoles were identified as endobiotic and xenobiotic ligands of human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhR. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist or antagonist activities of tested compounds, having substantially variable EC50, IC50 and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of AhR were 4-Me-indole (134%), 6-Me-indole (91%) and 7-MeO-indole (80%), respectively. The most effective antagonists of AhR included 3-Me-indole (IC50 19 μM), 2,3-diMe-indole (IC50 11 μM) and 2,3,7-triMe-indole (IC50 12 μM). RT-PCR analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. Compound leads, 4-Me-indole and 7-MeO-indole, induced substantial nuclear translocation of AhR and enriched binding of AhR to CYP1A1 promoter, as observed using fluorescent immune-histochemistry and chromatin immunoprecipitation assays, respectively. Molecular modeling and docking studies suggest that the agonists and antagonists likely share the same binding pocket but have unique binding modes that code for their affinity. Binding pocket analysis further revealed that 4-methylindole and 7-methoxyindole can simultaneously bind to the pocket and produce synergistic interactions. Together these data show a dependence on subtle and specific chemical indole structures as AhR modulators and furthermore underscore the importance of complete evaluation of indole compounds as nuclear receptor ligands.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Molecular Pharmacology
ISSN
0026-895X
e-ISSN
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Volume of the periodical
93
Issue of the periodical within the volume
6
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
631-644
UT code for WoS article
000435117100008
EID of the result in the Scopus database
2-s2.0-85052989368