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Development of novel aryl hydrocarbon receptor antagonists
Author(s) -
Swanson Hollie Isabel,
Choi EunYoung,
Lee Hyosung,
Dingle R.W. Cameron,
Kim KungBo
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.757.10
Subject(s) - aryl hydrocarbon receptor , agonist , chemistry , ligand (biochemistry) , receptor , downregulation and upregulation , aryl , pharmacology , microbiology and biotechnology , biology , biochemistry , transcription factor , gene , alkyl , organic chemistry
Increasing evidence indicates that the aryl hydrocarbon receptor (AHR) plays a role in the development and progression of human chronic diseases. Thus, developing appropriate antagonists that target the AHR may not only provide tools to better understand how the AHR signaling pathway modifies human diseases but may ultimately result in novel pharmacological interventions. With this in mind, we have synthesized and characterized a privileged library of putative AHR antagonists that represent derivatives of CH‐223191. Ligand binding analyses have identified at least three derivatives that exhibit equal to or higher ligand binding affinity that the parent compound, CH‐223191. Using reporter assays and mRNA expression analyses, we have found that these CH‐223191 derivatives are not only effective at blocking TCDD‐induced and basal AHR activity, but display minimal agonistic properties. Interestingly, one derivative, AL‐3 appears to synergize with the AHR agonist TCDD with respect to AHR activity. Taken together, these data set the stage for understanding the rules by which optimal AHR antagonists may be developed. This work is supported by ES014849