1,721,016 research outputs found
An efficient substitution reaction for the preparation of thyroid hormone analogues
No full textThe substitution of the sterically hindered carbon of the potent thyroid hormone agonist, GC-1, was effected by a reaction based on the solvolysis of the benzylic hydroxyl group. The reaction was found to proceed in high yield with a variety of nucleophiles including alcohols, thiols, allyl silanes and electron-rich aromatic compounds, providing a convenient route to the synthesis of new thyroid hormone analogues
Improved synthesis of the iodine-free thyromimetic GC-1
No full textSynthesis of the TRbeta-selective thyromimetic GC-1 has been improved using methoxymethyl (MOM) and triisopropylsilyl (TiPS) substituents as phenolic protecting groups. The new synthetic route is adaptable to analogue design
Molecular mechanisms underlying thyroid hormone induced gene expression cascades during amphibian metamorphosis.
No full textSynthesis and biological activity of novel thyroid hormone analogues: 5 '-aryl substituted GC-1 derivatives
No full textCompounds that selectively modulate thyroid hormone action by functioning as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be useful for medical therapy. We have synthesized a high affinity TRbeta-selective agonist ligand, GC-1, and optimized the synthetic route to provide large quantities of the compound for animal testing. In addition to an improvement in efficiency, the new synthetic route offers a chemical handle for selective modification of the thyronine skeleton to produce new derivatives. To explore the effect of GC-1 core structure modifications on binding to TR isoforms and activation of transcription, we developed here an efficient and flexible route to a new series of 5'-substituted GC-1 analogues. This route relies on ortho lithiation and in situ boration of the biarylmethane compound 1, a key intermediate of the revised GC-1 synthesis, followed by Suzuki cross-coupling. Using this approach we prepared and tested eleven 5'-substituted GC-1 analogues. Substitution at the 5'-position decreased binding affinity, but retained TRbeta-selectivity for most of the compounds. Transactivation assays reveal that most of these compounds function as thyroid hormone agonists, but one compound (GC-14) antagonizes the response to thyroid hormone
Induction of larval tissue resorption in Xenopus laevis tadpoles by the thyroid hormone receptor agonist GC-1
No full textA major challenge in understanding nuclear hormone receptor function is to determine how the same ligand can cause very different tissue-specific responses. Tissue specificity may result from the presence of more than one receptor subtype arising from multiple receptor genes or alternative splicing. Recently, high affinity analogs of nuclear receptor ligands have been synthesized that show subtype selectivity. These analogs can greatly facilitate the study of receptor subtype-specific functions in organisms where mutational analysis is problematic or where it is desirable for receptors to be expressed in their normal physiological contexts. We describe here the effects of the synthetic thyroid hormone analog GC-1 on the metamorphosis of the frog Xenopus laevis. The most potent natural thyroid hormone, 3,5,3'-triidothyronine or T3, shows similar binding affinity and transactivation dose-response curves for both thyroid hormone receptor isotypes, designated TRalpha and TRbeta. GC-1, however, binds to and activates TRbeta at least an order of magnitude better than it does TRalpha. GC-1 efficiently induces death and resorption of premetamorphic tadpole tissues such as the gills and the tail, two tissues that strongly induce thyroid hormone receptor beta during metamorphosis. GC-1 has less effect on the growth of adult tissues such as the hindlimbs, which express high TRalpha levels. The effectiveness of GC-1 in inducing tail resorption and tail gene expression correlates with increasing TRbeta levels. These results illustrate the utility of subtype selective ligands as probes of nuclear receptor function in vivo
A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor
No full textAbstract
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
Effects of the Thyroid Hormone Receptor Agonist GC-1 on Metabolic Rate and Cholesterol in Rats and Primates: Selective Actions Relative to 3,5,3'-Triiodo-L-Thyronine (T3)
No full textCurrent drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype beta (TRbeta) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal tachycardia after TRbeta stimulation. For these studies, the TRbeta selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED(50) = 190 nmol/kg x d) approximately 30 times more potently than it induced tachycardia (ED(15) = 5451 nmol/kg x d). T(3) showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED(5) = 477 nmol/kg x d) relative to tachycardia compared with T(3), which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T(3) and GC-1, whereas no tachycardia was observed for GC-1, unlike T(3). T(3) and GC-1 caused a significant (approximately 4%) reduction in body weight in these animals. Therefore, selective TRbeta activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a)
Modulation of cardiac inotropic state by non-nuclear rapid-acting thyroid hormone metabolites
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Modulation of cardiac inotropic state by 3-iodothyronamine: evidence for a novel signalling pathway mediated by trace amine-associated receptors
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