Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Analogs of the TRalpha-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 TRalpha, all analogs display TRalpha-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 TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
Ocasio
Cory A
CA
Chemistry and Chemical Biology Graduate Program, University of California-San Francisco, 600 16th Street, San Francisco, CA 94143-2280, USA.
Scanlan
Thomas S
TS
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D008675:Metamorphosis, Biological / Q000187:drug effects*; D015394:Molecular Structure; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014982:Xenopus laevis
C517607:5-(3,5-diiodo-4-(3-isopropyl-4-hydroxyphenoxy)benzyl)imidazolidine-2,4-dione; D006827:Hydantoins; D037021:Thyroid Hormone Receptors alpha