Characterization of thyroid hormone receptor α (TRα)-specific analogs with varying inner- and outer-ring substituents

Analogs of the TRα-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3′ position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRα, all analogs display TRα-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6–12-fold preference in transactivation when tested with TRα in HeLa cells. One analog, CO24, showed in vivo TRα-specific action in a tadpole metamorphosis assay.

CO23 displays TRα-specificity in vitro and in vivo. Compound CO23 analogs with greater specificity may prove superior to CO23 in treating heart disease or as a pharmacological probe of TR biology.Figure optionsDownload as PowerPoint slide