A HIGH-AFFINITY SUBTYPE-SELECTIVE AGONIST LIGAND FOR THE THYROID-HORMONE RECEPTOR

Background: Thyroid hormones regulate many different physiological pro cesses in different tissues in vertebrates. Most of the actions of thy roid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated t ranscription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often cc-e xpressed at different levels in different tissues. Most thyroid hormon es do not discriminate between the two TRs and bind both with similar affinities. Results: We have designed and synthesized a thyroid hormon e analog that has high affinity for the TRs and is selective in both b inding and activation functions for TR beta over TR alpha, The compoun d, GC-I, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural c hanges with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T-3). These changes include replacement of the three iodines with met hyl end 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 s how that GC-I is a member of a new class of thyromimetic compounds tha t are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. T he TR beta selectivity of GC-I is particularly interesting and suggest s that GC-I might be a useful in vivo probe for studying the physiolog ical roles of the different thyroid hormone receptor isoforms.