Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties.

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the role of the AHR in normal physiology is still an area of intense investigation. For example, this receptor plays an important role in certain immune responses. We have previously determined that the AHR can mediate repression of acute-phase genes in the liver. For this observation to be therapeutically useful, selective activation of the AHR would likely be necessary. Recently, the selective estrogen receptor ligand WAY-169916 has also been shown to be a selective AHR ligand. WAY-169916 can efficiently repress cytokine-mediated acute-phase gene expression (e.g., SAA1) yet fail to mediate a dioxin response element-driven increase in transcriptional activity. The goals of this study were to structurally modify WAY-169916 to block binding to the estrogen receptor and increase its affinity for the AHR. A number of WAY-169916 derivatives were synthesized and subjected to characterization as AHR ligands. The substitution of a key hydroxy group for a methoxy group ablates binding to the estrogen receptor and increases its affinity for the AHR. The compound 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA 360), in particular, exhibited essentially no AHR agonist activity yet was able to repress cytokine-mediated SAA1 gene expression in Huh7 cells. SGA 360 was tested in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated ear inflammatory edema model using C57BL6/J and Ahr(-/-) mice. Our findings indicate that SGA 360 significantly inhibits TPA-mediated ear swelling and induction of a number of inflammatory genes (e.g., Saa3, Cox2, and Il6) in C57BL6/J mice. In contrast, SGA 360 had no effect on TPA-mediated ear swelling or inflammatory gene expression in Ahr(-/-) mice. Collectively, these results indicate that SGA 360 is a selective Ah receptor modulator (SAhRM) that exhibits anti-inflammatory properties in vivo.

• Authors: Iain A Murray, Gowdahalli Krishnegowda, Brett C DiNatale, Colin Flaveny, Chris Chiaro, Jyh-Ming Lin, Arun K Sharma, Shantu Amin, Gary H Perdew
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 23 Issue 5 Pg. 955-66 (May 17 2010) ISSN: 1520-5010 [Electronic] United States
• PMID: 20423157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Allyl Compounds
• Anti-Inflammatory Agents
• Indazoles
• Interleukin-6
• Ligands
• Pyrazoles
• RNA, Messenger
• Receptors, Aryl Hydrocarbon
• Receptors, Estrogen
• SGA 360
• Saa2 protein, mouse
• Saa3 protein, mouse
• Serum Amyloid A Protein
• WAY-169916
• Cyclooxygenase 2
• Tetradecanoylphorbol Acetate

Topics

• Allyl Compounds (chemistry, pharmacology)
• Animals
• Anti-Inflammatory Agents (chemical synthesis, chemistry, pharmacology)
• Cyclooxygenase 2 (metabolism)
• Gene Expression Regulation
• Hep G2 Cells
• Humans
• Indazoles (chemistry, pharmacology)
• Interleukin-6 (metabolism)
• Ligands
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Otitis (chemically induced, drug therapy)
• Pyrazoles (chemistry)
• RNA, Messenger (metabolism)
• Receptors, Aryl Hydrocarbon (agonists, genetics, metabolism)
• Receptors, Estrogen (antagonists & inhibitors, metabolism)
• Serum Amyloid A Protein (metabolism)
• Tetradecanoylphorbol Acetate (toxicity)