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

Analogs of the TR alpha-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 TR alpha, all analogs display TR alpha-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 TR alpha in HeLa cells. One analog, CO24, showed in vivo TR alpha-specific action in a tadpole metamorphosis assay. (c) 2007 Elsevier Ltd. All rights reserved.