Interactions of synthetic estrogens with human estrogen receptors

Synthetic estrogens have diverse chemical structures and may either positively or negatively affect the estrogenic signaling pathways through interactions with the estrogen receptors (ERs). Modeling studies suggest that 4-(1-adamantyl)phenol (AdP) and 4,4′-(1,3-adamantanediyl)diphenol (AdDP) can bind in the ligand binding site of ERα. We used fluorescence polarization (FP) to compare the binding affinities of AdP, AdDP and 2-(1-adamantyl)-4-methylphenol (AdMP) for human ERα and ERβ with the binding affinities of the known ER ligands, diethylstilbestrol (DES) and 4-hydroxytamoxifen (4OHT). Competition binding experiments show that AdDP has greater affinity for both ERs than does AdP, while AdMP does not bind the receptor proteins. The relative binding affinities of AdDP and AdP are weaker than the affinity of DES or 4OHT for both ERs with the exception of AdDP, which binds ERβ with higher affinity than does 4OHT. We also found that AdDP and AdP cause differential conformational changes in ERα and ERβ, which result in altered affinities of the ERs for fluorescein-labeled estrogen response elements (EREs) using a direct binding FP assay. The results show that ERβ liganded with either AdDP or AdP has greater affinity for human pS2 ERE than the ERβ-4OHT complex. The data suggest that synthetic molecules like adamantanes may function as biologically active ligands for human ERs. This demonstrates the importance of considering the potential of novel classes of synthetic compounds as selective ER modulators.