Studies of antagonists and selective agonists of the thyroid hormone receptors

The modulation of the thyroid hormone receptors (TRs) by selective activators and inactivators has potential utility in medicine and in the study of the biological roles of the receptors. The design and synthesis of analogues of GC-1, an easily prepared high-affinity TRP-selective thyromimetic, are the focus of this thesis.; The design principles used in the estrogen receptor antagonist ICI-164,384 were applied to GC-1 to produce a TR antagonist. Methods were devised for the preparation of GC-1 analogues bearing substitutents at the carbon atom bridging the two aromatic rings. This position for derivatization is unavailable in thyroid hormone, where an oxygen atom joins the two aromatic rings. A series of bridge-substituted GC-1 analogues were synthesized and characterized. Substitution at the bridging carbon results in a substantial loss of affinity for TR; however, the GC-1 analogue bearing the same alkylamide side chain as ICI-164,384 retains some affinity for TR and functions as a competitive antagonist of T₃ in cell-based assays of transcription activation.; The structural features of GC-1 that confer its greater TR affinity and selectivity compared to DIMIT were also analysed. GC-1 was designed as an analogue of the thyromimetic DIMIT, which has a lower affinity for TR and is not selective. GC-1 has a methylene group linking its two aromatic rings and an oxyacetic acid polar side chain, while DIMIT has an ether oxygen linking its aromatic rings and an L-alanine polar side chain. To identify the important factors, analogues were prepared which bear only one of their two different structural features. The analogue of GC-1 with a biaryl ether has comparable selectivity to GC-1, while the analogue of DIMIT with a methylene group linking its aromatic rings is only slightly selective. These results demonstrate that the oxyacetic acid side chain of GC-1 is critical in conferring TRβ-selectivity.