A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.
BACKGROUND
Thyroid hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities.


RESULTS
We have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TR beta over TR alpha. The compound, GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain.


CONCLUSIONS
The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TR beta selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different thyroid hormone receptor isoforms.
Chiellini
G
G
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
Apriletti
J W
JW
Yoshihara
H A
HA
Baxter
J D
JD
Ribeiro
R C
RC
Scanlan
T S
TS
D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D010636:Phenols; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000819:agonists / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine