TY - JOUR T1 - Development of Novel CH223191-Based Antagonists of the ARYL Hydrocarbon Receptor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.073643 SP - mol.111.073643 AU - Eun-Young Choi AU - Hyosung Lee AU - R.W. Cameron Dingle AU - KyungBo Kim AU - Hollie Swanson Y1 - 2011/10/03 UR - http://molpharm.aspetjournals.org/content/early/2011/10/03/mol.111.073643.abstract N2 - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates genes involved in drug/xenobiotic metabolism, cell cycle progression, cell fate determination, immune function and the inflammatory response. The increasing evidence that the AHR plays a role in the pathophysiology of a number of human disease states is driving the need for improved pharmacological tools to be used for understanding the in vivo impact of AHR modulation. In this study, we have characterized and employed a structure-activity-relationship analyses of a newly synthesized library of derivatives of the potent AHR antagonist CH223191. Initial screening of these compounds revealed that those bearing groups with strong electronegativity at the R1 position (CHD-5, CHD-11 and CHD-12) versus those that are more electron-poor at this position (i.e., CHD-7 and CHD-8) elicited the most potent AHR antagonistic properties. The ability of these derivatives to inhibit agonist (2,3,7,8 tetrachlorodibenzo-p-dioxin) binding, nuclear translocation of the AHR and agonist-induced enzyme activity were also determined and support the initial findings. Further, CH223191, but not CHD-5, CHD-11 and CHD-12 was found to exhibit AHR-independent pro-proliferative properties. These results contribute to our understanding of the structural requirements of potent AHR antagonists and the development of effective pharmacological tools to be used for studying the pathophysiological role of the AHR. ER -