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Research ArticleCellular and Molecular

Identification of a High-Affinity Ligand That Exhibits Complete Aryl Hydrocarbon Receptor Antagonism

Kayla J. Smith, Iain A. Murray, Rachel Tanos, John Tellew, Anthony E. Boitano, William H. Bisson, Siva K. Kolluri, Michael P. Cooke and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 318-327; DOI: https://doi.org/10.1124/jpet.110.178392
Kayla J. Smith
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Iain A. Murray
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Rachel Tanos
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John Tellew
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Anthony E. Boitano
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William H. Bisson
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Siva K. Kolluri
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Michael P. Cooke
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Gary H. Perdew
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Abstract

The biological functions of the aryl hydrocarbon receptor (AHR) can be delineated into dioxin response element (DRE)-dependent or -independent activities. Ligands exhibiting either full or partial agonist activity, e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin and α-naphthoflavone, have been demonstrated to potentiate both DRE-dependent and -independent AHR function. In contrast, the recently identified selective AHR modulators (SAhRMs), e.g., 1-allyl-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (SGA360), bias AHR toward DRE-independent functionality while displaying antagonism with regard to ligand-induced DRE-dependent transcription. Recent studies have expanded the physiological role of AHR to include modulation of hematopoietic progenitor expansion and immunoregulation. It remains to be established whether such physiological roles are mediated through DRE-dependent or -independent pathways. Here, we present evidence for a third class of AHR ligand, “pure” or complete antagonists with the capacity to suppress both DRE-dependent and -independent AHR functions, which may facilitate dissection of physiological AHR function with regard to DRE or non-DRE-mediated signaling. Competitive ligand binding assays together with in silico modeling identify N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351) as a high-affinity AHR ligand. DRE-dependent reporter assays, in conjunction with quantitative polymerase chain reaction analysis of AHR targets, reveal GNF351 as a potent AHR antagonist that demonstrates efficacy in the nanomolar range. Furthermore, unlike many currently used AHR antagonists, e.g., α-naphthoflavone, GNF351 is devoid of partial agonist potential. It is noteworthy that in a model of AHR-mediated DRE-independent function, i.e., suppression of cytokine-induced acute-phase gene expression, GNF351 has the capacity to antagonize agonist and SAhRM-mediated suppression of SAA1. Such data indicate that GNF351 is a pure antagonist with the capacity to inhibit both DRE-dependent and -independent activity.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES04869].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.178392.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AHR
    aryl hydrocarbon receptor
    ARNT
    AHR nuclear translocator
    SAhRM
    selective AHR modulator
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    DRE
    dioxin response element
    TH
    T helper
    DMSO
    dimethyl sulfoxide
    IL
    interleukin
    PCR
    polymerase chain reaction
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    PAL
    2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin
    GNF351
    N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine
    SGA360
    1-allyl-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole
    αNF
    α-naphthoflavone
    MNF
    3′-methoxy-4′-nitroflavone
    TMF
    6,2′,4′-trimethoxyflavone
    CH-223191
    2-methyl-2H-pyrazole-3-carboxylic acid(2-methyl-4-o-tolylazo-phenyl)-amide
    SR1
    4-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol
    I3S
    3-indoxyl-sulfate
    WAY-69916
    4-[1-allyl-7-(trifluoromethyl)-1H-indazol-3yl]benzene-1.

  • Received December 18, 2010.
  • Accepted March 16, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleCellular and Molecular

Identification of a High-Affinity Ligand That Exhibits Complete Aryl Hydrocarbon Receptor Antagonism

Kayla J. Smith, Iain A. Murray, Rachel Tanos, John Tellew, Anthony E. Boitano, William H. Bisson, Siva K. Kolluri, Michael P. Cooke and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 318-327; DOI: https://doi.org/10.1124/jpet.110.178392

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Research ArticleCellular and Molecular

Identification of a High-Affinity Ligand That Exhibits Complete Aryl Hydrocarbon Receptor Antagonism

Kayla J. Smith, Iain A. Murray, Rachel Tanos, John Tellew, Anthony E. Boitano, William H. Bisson, Siva K. Kolluri, Michael P. Cooke and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 318-327; DOI: https://doi.org/10.1124/jpet.110.178392
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