Characterization of the Antiallergic Drugs 3-[2-(2-Phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic Acid and Ethyl 3-Hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as Full Aryl Hydrocarbon Receptor Agonists

Morales, J. Luis; Krzeminski, Jacek; Amin, Shantu; Perdew, Gary H.

doi:10.1021/tx700350v

Cited by 14 publications

(9 citation statements)

References 66 publications

(110 reference statements)

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“…These agonists cause substantial up‐regulation of AHR battery genes, but only within hours of treatment 103,108 . In comparison, TCDD causes long‐term stimulation of AHR that can be measured days after administration 109–111 . Differences in the length of AHR stimulation may lead to differences in AHR‐mediated biology.…”

Section: Considerations For Future Experimentsmentioning

confidence: 99%

The aryl hydrocarbon receptor: a perspective on potential roles in the immune system

2009

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Summary The aryl hydrocarbon receptor (AHR) is a protein best known for its role in mediating toxicity. Over 30 years of research has uncovered additional roles for the AHR in xenobiotic metabolism and normal vascular development. Activation of the AHR has long been known to cause immunotoxicity, including thymic involution. Recent data suggesting a role for the AHR in regulatory T‐cell (Treg) and T‐helper 17 (Th17) cell development have only added to the excitement about this biology. In this review, we will attempt to illustrate what is currently known about AHR biology in the hope that data from fields as diverse as evolutionary biology and pharmacology will help elucidate the mechanism by which AHR modifies immune responses. We also will discuss the complexities of AHR pharmacology and genetics that may influence future studies of AHR in the immune system.

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Section: Considerations For Future Experimentsmentioning

confidence: 99%

The aryl hydrocarbon receptor: a perspective on potential roles in the immune system

2009

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“…Two antiallergenic drugs, 3-[2-(2-phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic acid (M50367) and ethyl 3-hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl] propanoate (M50354), are AHR receptor agonists in vivo and in vitro (71, 72). The immunosuppressive effects of M50354 were shown to depend on the AHR as the immune response of AHR −/− mice was not affected by treatment with the drug (71).…”

Section: Immune Effects Of Non-tcdd Ahr Ligandsmentioning

confidence: 99%

AHR-mediated immunomodulation: The role of altered gene transcription

Kerkvliet

2009

Biochemical Pharmacology

152

138

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The immune system is a sensitive target for aryl hydrocarbon receptor (AHR)-mediated transcriptional regulation. Most of the cells that participate in immune responses express AHR protein, and many genes involved in their responses contain multiple DRE sequences in their promoters. However, the potential involvement of many of these candidate genes in AHR-mediated immunomodulation has never been investigated. Many obstacles to understanding the transcriptional effects of AHR activation exist, owing to the complexities of pathogen-driven inflammatory and adaptive immune responses, and to the fact that activation of AHR often influences the expression of genes that are already being regulated by other transcriptional events in responding cells. Studies with TCDD as the most potent, non-metabolized AHR ligand indicate that AHR activation alters many inflammatory signals that shape the adaptive immune response, contributing to altered differentiation of antigen specific CD4 + T helper (TH) cells and altered adaptive immune responses. With TCDD, most adaptive immune responses are highly suppressed, which has been recently linked to the AHR-dependent induction of CD4+CD25+ regulatory T cells. However activation of AHR by certain non-TCDD ligands may result in other immune outcomes, as a result of metabolism of the ligand to active metabolites or to unknown ligand-specific effects on AHR-mediated gene transcription. Based on studies using AHR−/− mice, evidence for a role of endogenous AHR ligands in regulation of the immune response is growing, with bilirubin and lipoxinA4 representing two promising candidates.

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“…The AHR can play a role in the balance of T H 1 and T H 2 cells, this was established through the use of an AHR agonist M50367 that mediates a preference for increased T H 1 versus T H 2 cells (11, 12). M50367 exposure in mice leads to a decreased response in an allergic experimental model.…”

Section: Introductionmentioning

confidence: 99%

Development of a Selective Modulator of Aryl Hydrocarbon (Ah) Receptor Activity that Exhibits Anti-Inflammatory Properties

Murray

Gowda

DiNatale

et al. 2010

Chem. Res. Toxicol.

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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, 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.

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Characterization of the Antiallergic Drugs 3-[2-(2-Phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic Acid and Ethyl 3-Hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as Full Aryl Hydrocarbon Receptor Agonists

Cited by 14 publications

References 66 publications

The aryl hydrocarbon receptor: a perspective on potential roles in the immune system

The aryl hydrocarbon receptor: a perspective on potential roles in the immune system

AHR-mediated immunomodulation: The role of altered gene transcription

Development of a Selective Modulator of Aryl Hydrocarbon (Ah) Receptor Activity that Exhibits Anti-Inflammatory Properties

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