Interactions of synthetic estrogens with human estrogen receptors

Synthetic estrogens have diverse chemical structures and may either positiv ely or negatively affect the estrogenic signaling pathways through interact ions with the estrogen receptors (ERs). Modeling studies suggest that 4-(1- adamantyl)phenol (AdP) and 4,4 '-(1,3-adamantanediyl)diphenol (AdDP) can bi nd in the ligand binding site of ER alpha. We used fluorescence polarizatio n (FP) to compare the binding affinities of AdP, AdDP and 2-(1-adamantyl)-4 -methylphenol (AdMP) for human ER alpha and ER beta with the binding affini ties of the known ER ligands, diethylstilbestrol (DES) and 4-hydroxytamoxif en (4OHT). Competition binding experiments show that AdDP has greater affin ity for both ERs than does AdP, while AdMP does not bind the receptor prote ins. The relative binding affinities of AdDP and AdP are weaker than the af finity of DES or 4OHT for both ERs with the exception of AdDP, which binds ER beta with higher affinity than does 4OHT. We also found that AdDP and Ad P cause differential conformational changes in ER alpha and ER beta, which result in altered affinities of the ERs for fluorescein-labeled estrogen re sponse elements (EREs) using a direct binding FP assay. The results show th at ER beta liganded with either AdDP or AdP has greater affinity for human pS2 ERE than the ER beta -4OHT complex. The data suggest that synthetic mol ecules like adamantanes may function as biologically active ligands for hum an ERs. This demonstrates the importance of considering the potential of no vel classes of synthetic compounds as selective ER modulators.