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

Chemical Research in Toxicology
José Luis MoralesGary H Perdew

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates most of the toxic effects of numerous chlorinated (e.g., TCDD) and nonchlorinated polycyclic aromatic compounds (e.g., benzo[ a]pyrene). Studies in AhR null mice suggested that this receptor may also play a role in the modulation of immune responses. Recently, two drugs, namely, M50354 and M50367 (ethyl ester derivative of M50354), were described as AhR ligands with high efficacy toward reducing atopic allergic symptoms in an AhR-dependent manner by skewing T helper cell differentiation toward a T H1 phenotype [Negishi et al. (2005) J. Immunol. 175 (11), 7348-7356]. Surprisingly, these drugs were shown to have minimal activity toward inducing classical dioxin responsive element-driven AhR-mediated CYP1A1 transcription. We synthesized and reevaluated the ability of these drugs to regulate AhR activity. In contrast to previously published data, both M50354 and M50367 were found to be potent inducers of several AhR target genes, namely, CYP1A1, CYP1B1, and UGT1A2. M50367 was a more effective agonist than M50354, perhaps accounting for its higher bioavailability in vivo. However, M50354 was capable of displacing an AhR-specific radioligand ...Continue Reading

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Citations

Nov 10, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Curtis J OmiecinskiJeffrey M Peters
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Oct 17, 2019·Inflammopharmacology·Xiao-Song WangHai-Feng Pan
Sep 10, 2020·International Journal of Molecular Sciences·Anna WajdaAgnieszka Paradowska-Gorycka

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