While our data, hence, demonstrate direct modulation of the TLX LBD by xanthines, the molecular mechanism of this TLX activity will require future attention to confirm the ligand binding site and capture stabilizing or destabilizing effects of ligand binding that contribute to the modulation of TLX activity. We hypothesize that several molecular factors, including but likely not limited to heterodimerization with RXR and SMRT interactions, involve in the regulation of cellular TLX activity by xanthines. The higher potency we have observed for istradefylline in modulating TLX in cells compared to cell-free assays may hence be explained by the sum of several weaker contributions that cooperate in cellular environment. Further elucidation of this coregulatory network of TLX and its response to ligand binding is needed for which the xanthines present as useful tool.