Thyroid hormone antagonists

Propylthiouracil [PTU] [Antithyroid Agent/Thyroid Hormone Antagonist] Uses HypCTthyroidism Action X Production of Tg T4 conversion of T4 to Tg Dose Adults. Initial 100 mg PO q8h (may need up... 

The PASS system included 31 thyroid hormone antagonists, the identities of which have not been published. It is likely that many of them contain thiol functionalities, such as are present in known thyroid hormone antagonists. This limitation notwithstanding, the PASS system analysis showed that most of the 536... 

Lim, W., N.-H. Nguyen, H.Y. Yang, T.S. Scanlan and J.D. Furlow. A thyroid hormone antagonist that inhibits thyroid hormone action in vivo. J. Biol. Chem. 277 35664-35670, 2002. 

Cunha Lima, S.T., Webb, P., Baxter, J.D. and Scanlan, T.S. (2002) Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. Journal of Medicinal Chemistry, 45, 3310—3320. 

Methimazole (15 to 60 mg p.o. daily until patients are euthyroid) is indicated in the treatment of hyperthyroidism. Propylthiouracil, carbimazole, and methimazole, thyroid hormone antagonists, exert their effects by inhibiting iodide organification, and by inhibiting the formation of diiodo-thyronine (DIT) (see Figure 66). 

Propylthiouracil, a thyroid hormone antagonist, is used in hyperthyroidism, in thyrotoxic crisis, and in preparation for thyroidectomy (see also Figure 66). 

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

Peripheral Antagonists. The relatively long duration of action of the thyroid hormones makes it desirable to have compounds capable of blocking them competitively at their site of action. This is desirable in the treatment of thyroid storm where the reduction of circulating hormone levels brought about by the inhibition of their synthesis is too slow. 

A large number of thyroid hormone analogues have been tested for this effect (6). Among others, i-T (3) and 3,3 -T2 (5) and their propionic acid side-chain analogues decrease oxygen consumption at molar ratios of 50—200 1 of T. Nevertheless, no potent or clinically usehil peripheral antagonists have been found. 

R, Samuels HH. Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking. Proc Natl Acad Sci USA 2003 100 7354-9. 

Thyroid hormone receptor antagonists, IC50 20 PM (upper), 0.75 fiM (lower) from structure-based virtual screening... 

A similar approach was used toward the identification of antagonists of the thyroid hormone receptor [265]. Again, a model of this receptor in its predicted antagonist-bound conformation served to select 100 antagonist candidates out of a library of 250000 compounds. Fourteen of 75 tested molecules were found to antagonize this... 

Schriks, M., Vrabie, C.M., Gutleb, A.C., Faassen, E., Rietjens, I.M.C.M, Murk, A.J. (2006). T-screen to quantify potentiating, antagonistic and thyroid hormone-like activities of poly halogenated aromatic hydrocarbons (PHAHs). Toxicology in vitro, Vol 20, no 4,490-498. 

Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones for example, thyroid hormones increase both the number of 3 receptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a 3-adrenoceptor antagonist, in ameliorating symptoms of this disease. 

While they are often prescribed, the lower costs of codeine, ACE inhibitors, beta-blockers, thyroid hormones, calcium blockers, and benzodiazepines keep them off the list of top sales. Conversely, the higher cost of erythropoietins, antineo monoclonal antibodies, angiotensin II antagonists, antiarthritis drugs, and bisphosphonates put them on the list of top sales but not top prescriptions. 

The effect of beta-adrenoceptor antagonists on thyroid hormone metabolism is unlikely to play a significant role... 

Toxicologically the function of the terminal hormones of endocrine cascades (i.e., steroid, retinoid, thyroid hormones) appear to be most susceptible to disruption by chemicals. This is because many foreign molecules share sufficient characteristics with these hormone molecules to allow binding to the nuclear receptors of these hormones in either an agonistic or antagonistic fashion. The binding of the xenobiotic to the... 

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