Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including CO presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, o-cresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR pan-antagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.

Department of Biochemistry Faculty of Science Palacký University Šlechtitelů 27 Olomouc 779 00 Czech Republic

Department of Cell Biology and Genetics Faculty of Science Palacký University Šlechtitelů 27 Olomouc 779 00 Czech Republic

Department of Medicine and Genetics Albert Einstein College of Medicine Bronx NY 10461 USA

Department of Organic Chemistry Faculty of Science Palacký University 17 Listopadu 12 Olomouc 771 46 Czech Republic

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 Brno 612 00 Czech Republic

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