Chemistry

A. Endogenous Hormones

The mammalian thyroid gland biosynthesizes, stores, and secretes two molecular species of thyroid hormones. They are thyroxine (T4) or l-3,5,3',5'-tetraio-dothyronine and triiodothyronine (T3) or l-3,5,3'-triiodothyronine (see Figure 6-3). The parent compound for the iodinated series of thyroid-active hormones is thyronine. Thyronine is 4-(4'-hydroxy-phenoxy)-l-phenylalanine; the conventional numbering system for the carbon atoms of the thyronine molecule is also indicated in Figure 6-3.

B. Thyroid Hormone Analogs

A detailed study of the structural requirements for thyromimetic action suggests that thyroid hormone "active" compounds must have, at a minimum, a central lipophilic core containing bulky 3,5, and 3' substit-uents (not necessarily iodine atoms) and two anion groups at each distal end of the molecule. Thus, extensive structural modification of the molecule is possible without a major loss of biological activity. Methyl groups, bromine, fluorine, and nitrate are tolerated with decreasing activity in the 3,5,3', and 5' positions, and the alanine side chain can be replaced by formate, acetate, propionate, or pyruvate groups with some decrease in, but not loss of, activity. Also, the ether link between the two phenolic rings can be replaced by a sulfur or methylene linkage. The biological properties of some thyroxine analogs are summarized in Table 6-1.

Thyroid-active compounds lacking a substitution in the 5' position have higher biological activity than those retaining a group at this position. Thus, triiodothyronine (T3) is some 5-8 times more active than tetra-iodothyronine (T4) (see Table 6-1). Compounds that are di- or trisubstituted but that lack two substituents in the first ring [e.g., 3,3',5'-triiodothyronine (reverse T3 or rT3), 3,3'-diiodothyronine, or 3',5'-diiodothyronine] usually have low or undetectable thyromimetic action.

Reverse T3 or 3,3',5'-triiodothyronine is present in low concentrations in the thyroid and blood. It is largely produced by peripheral monodeiodination of thyroxine (T4). Reverse T3 has only 10% of the thyromimetic activity of T4 and under some circumstances can antagonize the calorigenic effects of thyroxine.

FIGURE 6-2 Thyroid follicular epithelial cell and its adjacent follicle lumen (Fl). The cells have a well-developed Golgi apparatus, which is associated with the synthesis of thyroglobulin and its transport into the follicle lumen. Also, membrane-bound dense granules (Gr) and colloid droplets (CD) are present in the cytoplasm. [Reproduced with permission from Lentz, T. L. (1971). "Cell Fine Structure." W. B. Saunders, Philadelphia, PA.]

FIGURE 6-2 Thyroid follicular epithelial cell and its adjacent follicle lumen (Fl). The cells have a well-developed Golgi apparatus, which is associated with the synthesis of thyroglobulin and its transport into the follicle lumen. Also, membrane-bound dense granules (Gr) and colloid droplets (CD) are present in the cytoplasm. [Reproduced with permission from Lentz, T. L. (1971). "Cell Fine Structure." W. B. Saunders, Philadelphia, PA.]

Although d-thyroxine is not produced endoge-nously, the administration of this analog will result in 5-20% of the calorigenic response of L-thyroxine. Surprisingly, d-T3 and d-T4 have been found to bind in vitro to the nuclear thyroid receptor protein with the same high affinity as the comparable l compounds. Thus, the differences in activity of the d compounds between in vivo and in vitro systems may relate to differences in blood transport or tissue metabolism.

The acetic acid analogs derived from T3 and T4, namely, tri- or tetraiodothyroacetic acid (TRIAC or TETRAC) (see Figure 6-3), are physiologically important since they are known to be produced endoge-

nously by deamination and decarboxylation of the parent compound.

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