1nax
Thyroid receptor beta1 in complex with a beta-selective ligand
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OverviewOverview
Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine, (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant, effects on growth, development, and homeostasis in mammals. They regulate, important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and, overall sense of well being. The literature suggests many or most effects, of thyroid hormones on the heart, in particular on the heart rate and, rhythm, are mediated through the TRalpha(1) isoform, while most actions of, the hormones on the liver and other tissues are mediated more through the, TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be, therapeutically useful in nonthyroid disorders if adverse effects can be, minimized or eliminated. These potentially useful features include weight, reduction for the treatment of obesity, cholesterol lowering for treating, hyperlipidemia, amelioration of depression, and stimulation of bone, formation in osteoporosis. Prior attempts to utilize thyroid hormones, pharmacologically to treat these disorders have been limited by, manifestations of hyperthyroidism and, in particular, cardiovascular, toxicity. Consequently, development of thyroid hormone receptor agonists, that are selective for the beta-isoform could lead to safe therapies for, these common disorders while avoiding cardiotoxicity. We describe here the, synthesis and evaluation of a series of novel TR ligands, which are, selective for TRbeta(1) over TRalpha(1). These ligands could potentially, be useful for treatment of various disorders as outlined above. From a, series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity, and selectivity in a radioreceptor binding assay for the human thyroid, hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well, as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary, cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline, phosphatase reporter-gene downstream thyroid response element, (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the, R(1) position is substituted with acetic acid. Within this series, 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and, 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were, found to reveal the most promising in vitro data based on isoform, selectivity and were selected for further in vivo studies. The effect of, 2, 11a, and 15 in a cholesterol-fed rat model was monitored including, potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50))., Potency for tachycardia was significantly reduced for the TRbeta selective, compounds 11a and 15 compared with 2, while both 11a and 15 retained the, cholesterol-lowering potency of 2. This left an approximately 10-fold, therapeutic window between heart rate and cholesterol, which is consistent, with the action of ligands that are approximately 10-fold more selective, for TRbeta(1). We also report the X-ray crystallographic structures of the, ligand binding domains of TRalpha and TRbeta in complex with 15. These, structures reveal that the single amino acid difference in the ligand, binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a, slightly different hydrogen bonding pattern that may explain the increased, beta-selectivity of 15.
DiseaseDisease
Known diseases associated with this structure: Thyroid hormone resistance OMIM:[190160], Thyroid hormone resistance, autosomal recessive OMIM:[190160]
About this StructureAbout this Structure
1NAX is a Single protein structure of sequence from Homo sapiens with IH5 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1., Ye L, Li YL, Mellstrom K, Mellin C, Bladh LG, Koehler K, Garg N, Garcia Collazo AM, Litten C, Husman B, Persson K, Ljunggren J, Grover G, Sleph PG, George R, Malm J, J Med Chem. 2003 Apr 24;46(9):1580-8. PMID:12699376
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