Agonists of the aryl hydrocarbon receptor have been of interest to the pharmaceutical industry for many years. This interest originally stemmed from the observation that the AHR is a ligand-activated transcription factor that regulates the adaptive metabolism of xenobiotics and because receptor XL-184 binding is a known step in the carcinogenic and toxic action of environmental pollutants like 2,3,7,8-tetrachlorodibenzo-p-dioxin. Thus, agonism of the AHR has commonly been considered a signature for drugs that upregulate phase-I and phase-II metabolic systems and also for chemicals with pharmacological similarity to a known human carcinogen. As a result, AHR agonism has largely been considered a hazard signature for environmental chemicals and drugs in the pharmaceutical pipeline. Recent insights related to the normal physiological role of the AHR are changing our view of receptor agonism to one where agonism might be considered to hold therapeutic value. A number of recent reports are identifying new biological processes that might be influenced by endogenous receptor ligands. For example, descriptions of mice harboring a null allele at the Ahr locus indicate that receptor signaling plays an important role in normal cardiovascular development and function. The therapeutic potential related to this biology is demonstrated by the observation that potent AHR agonists like TCDD can correct developmental aberrations in hepatic blood flow under conditions of AHR hypomorphism. More recently, a role for the AHR in immunology has been emphasized by reports that activation of this receptor with ligands, such as TCDD, can lead to the generation of regulatory T-cells, while activation with other ligands, such as formylindolocarbazole can lead to Th17 cell formation. The potential clinical importance of this finding is supported by the observation that TCDD is able to ameliorate the symptoms of experimental autoimmune encephalomyelitis in mice, whereas FICZ aggravates this syndrome. Additional studies have supported the idea that Axitinib VEGFR/PDGFR inhibitor ligands can play a role in improving allograft acceptance after transplantation. The importance of the AHR in immunology has also been extended by a series of papers demonstrating the central importance of this receptor in the presence and maintenance of intraepithelial lymphocytes and lymphoid tissue inducer cells in the gut, highlighting that the AHR and its ligands play a role in normal physiology of the immune system and response to the outside environment. We have begun a search for agonists and antagonists of the AHR as part of an effort to develop a new class of receptor ligands with therapeutic potential for the treatment of vascular or immunological disease. Our initial strategy is to screen compounds that are pharmacologically well studied and that pose less environmental or health risks as compared to TCDD. Our approach to initially screen a library of compounds with known biological activity was chosen for three reasons. First, well studied compounds hold greater probability of prior toxicological and pharmacological characterization and thus may move into clinical 
settings more quickly. Second, identification of AHR ligands in classes of pharmacologically active compounds already in the clinic could shed additional insights into their mode of action, as well as identify compounds with understandable offtarget effects. Third, pharmacological information about novel AHR agonists could provide insight into the endogenous mechanism of action of this receptor or reveal the biological pathways in which the receptor participates during development.