Thyroid hormones structure-activity

Structure—Activity Relationships. In spite of the considerable synthetic and bioassay effort involved in estabhshing the thyromimetic potency of thyroid-hormone analogues, more than 100 compounds have been studied (Table 2). The main stmctural requirements for thyromimetic activity can be summarized as follows (6,12—16). 

On the other hand, some receptors are truly promiscuous in that they can activate two or more G-proteins from quite different classes, even in their normal cellular environment. For example, similar concentrations of thyroid-stimulating hormone (TSH 0.1-100 U/ml) can stimulate the incorporation of 32P-GTP into a, aQ, a12, a13, as, and aq/11 through activation of the thyrotropin receptor in membranes from human thyroid gland. TRH activation of Ca2+ currents in GH3 cells is obtunded equally by antisense-depletion of l2, aa, and aq/11, but not of aQ. Some individual genotypic P2y nucleotide receptors can also couple with equal affinity to PTx-sensitive and PTx-insensitive G-proteins in sympathetic neurons. The degree, or otherwise, of such promiscuity is presumably determined by the structure of the receptor protein itself. 

The normal form of interaction between receptor and DNA requires the hormone to have broken the native structure of the receptor and the dimer to have been formed. That is to say, the receptor-DNA interaction comes after the hormone-receptor interaction. Nevertheless, situations have been described in vitro in which the receptor is able to be previously associated to the HRE. This situation occurs in vivo for the thyroid hormone receptors, in which case it seems that the hormone-free dimer acts as an expression repressor of genes dependent on these hormones (Evans et al. 1988). The arrival of the hormone activates the dimer in situ and inverts its role as regulator. 

Within a programme aimed at the development of thyroid hormone analogues as potentially useful plasma cholesterol-lowering agents, the pyrida-zinone derivative SK F L-94901 (98) has been prepared and investigated in the U.K. [419-422]. Whereas naturally occurring thyroid hormones cannot be employed for this purpose because of their undesirable effect on heart rate, (98) has been found to represent a potent thyromimetic which retains hepatic activity but lacks cardiac activity. Structural modifications and QSAR studies have been carried out [422]. 

The structure-activity relationships of thyroid hormones and related structural analogs have been studied using both qualitative and quantitative methods, including the Hansch correlation. The structural requirements for receptor binding, and therefore hormone activity, are ... 

Mammals have several classes of hormones, distinguishable by their chemical structures and their modes of action (Table 23-1). Peptide, amine, and eicosanoid hormones act from outside the target cell via surface receptors. Steroid, vitamin D, retinoid, and thyroid hormones enter the cell and act through nuclear receptors. Nitric oxide also enters the cell, but activates a cytosolic enzyme, guanylyl cyclase (see Fig. 12-10). 

Thyroid hormones and their structural analogs showed lower DPPH-scavenging activity in comparison with butylated hydroxytoluene (BHT) as a standard compound. 3,5,3, 5 -tetraiodothyroacetic acid, 3,3,5 -triiodo-L-thyronine, and thyroxine showed the highest antioxidant activity measured by DPPH reduction, 3,5,3 5 -tetraiodothyroacetic acid having over 20% of the activity of BHT (05). 

A recently identified thyroid hormone cell surface receptor on the extracellular domain of integrin alphaVbeta (3) leads to the activation of the mitogen-activated protein kinase (MAPK) signal transduction cascade in human cell lines, Examples of MAPK-dependent thyroid hormone actions are plasma membrane ion pump stimulation and specific nuclear events, These events include serine phosphorylation of the nuclear thyroid hormone receptor, leading to co-activator protein recruitment and complex tissue responses, such as thyroid hormone-induced angiogenesis, The existence of this cell surface receptor means that the activity of the administered hormone could be limited through structural modification of the molecule to reproduce only those hormone actions initiated at the cell surface (8,9). 

Thiourea derivatives are known for their anti-thyroid effects due to inhibition of thyroid peroxidase [1], Two thiourea compounds especially, have found wide application in the treatment of patients with hyperthyroidism, i.e., PTU and 2-mer-capto-l-methylimidazole (methimazole). It was soon recognized, however, that while methimazole only blocks thyroid hormone synthesis PTU has an additional effect on thyroid hormone metabolism [13]. These clinical findings have been confirmed in vitro showing that PTU, but not methimazole, is a potent inhibitor of the type I deiodinase [5-8]. Structure-activity studies of thiourea analogues [44,45] have... 

Figure 2.6 Dorzolamide 16, a topically active carbonic anhydrase inhibitor, resulted from a structure-based ligand design it is used for the treatment of glaucoma. Sulfaguanidine 17 inhibits thyroid hormone biosynthesis. A phenylog of sulfanilamide 11 (Figure 2.4), dapsone 18, is used for the treatment of leprosy.

Polychlorinated diphenyl ethers (PCDE) are common impurities in chlorophenol formulations, which were earlier used as fungicides, slimicides, and as wood preservatives. PCDEs are structurally and by physical properties similar to polychlorinated biphenyls (PCB). They have low water solubility and are lipophilic. PCDEs are quite resistant to degradation and are persistent in the environment. In the aquatic environment, PCDEs bioaccumulate. These compounds are found in sediment, mussel, fish, bird, and seal. PCDEs show biomagnification potential, since levels of PCDEs increase in species at higher trophic levels. PCDEs are also detected in human tissue. Despite the persistence and bio accumulation, the significance of PCDEs as environmental contaminants is uncertain. The acute toxicity and Ah-receptor-me-diated (aryl hydrocarbon) activity of PCDEs is low compared to those of polychlorinated di-benzo-p-dioxins (PCDD) and dibenzofurans (PCDF). Due to structural similarity to thyroid hormone, PCDEs could bind to thyroid hormone receptor and alter thyroid function. Furthermore, PCDEs might be metabolized to toxic metabolites. In the environment, it is possible that photolysis converts PCDEs to toxic PCDDs and PCDFs. 

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