Selective Thyroid Hormone Receptor Ligands
Thyroid hormone receptors (TR) belong to the nuclear receptor superfamily of ligand activated transcription regulators and control the expression of target genes in virtually all tissues of the body. There are two genes that encode two different TRs (TRα and TRβ) that are expressed at different levels in different tissues. 3,5,3'-Triiodothyronine (T3) is the endogenous TR ligand, and T3 is unselective in the sense that it does not distinguish between TRα and TRβ even though the different receptor subtypes appear to have different roles in different tissues. We have discovered different chemical strategies for producing synthetic ligands that are selective for either TRα or TRβ. In addition, we have developed chemical strategies for converting activating (agonist) TR ligands into inactivating (antagonist) ligands that block the T3 induced functions of TR. These receptor selective ligands are useful tools for probing the tissue specific actions of TR and also serve as a starting point for the development of selective therapeutics that engage TR.
Thyroid Hormone Action in the Central Nervous System
In the central nervous system (CNS) thyroid hormone controls metabolism in all cell types that express TR and plays a key role in the development and maintenance of myelin, the protective lipid rich sheaths that encase the axons of neurons. Thus, thyroid hormone action is essential for normal development and maintenance of the brain. It has come to light recently that there are several CNS disorders that may benefit from CNS-selective thyroid hormone receptor modulation. These include Allan-Herndon-Dudley syndrome, which is a genetic disease that limits thyroid hormone transport across the blood-brain-barrier (BBB) as well as demyelination disorders such as multiple sclerosis (MS) and X-linked adrenoleukodystrophy (X-ALD). We are developing strategies for selective targeting of the CNS with thyroid hormone analogs and testing these agents in models of CNS diseases.
Thyroid Hormone Metabolites and Endogenous Derivatives
Thyroxine (T4), the major form of thyroid hormone biosynthesized in and secreted from the thyroid gland is converted into a rich variety of iodine-containing metabolites in the periphery. Many of these compounds have unique biological activities distinct from those of T3/T4 and the role played by these different chemical entities in vertebrate biology remains an open question. We have established an active program to identify and characterize these substances and address the important questions regarding how they are made and what activities they have, with the ultimate goal of elucidating their physiological function.