c-erboncogene; other family members include the vitamins A and D receptors and
steroid hormone receptors. The T 3 receptor exists in αandβforms; varying concentra-
tions of these two forms in different tissues permit the varying and subtle differences of
biological action of T 3 in different organ systems.
5.19.1.3 Structure–Activity Correlations
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:
- Two aromatic rings perpendicular to each other and separated by a spacer atom
(O, S, or C) that holds the rings at an angle of about 120°. - Halogen or methyl groups on the 3 and 5 positions of the ring that bears the alanine
side chain (these substituents keep the rings perpendicular to each other and partic-
ipate in hydrophobic bonding to the receptor). - An anionic side chain two or three carbons long, para to the bridging atom, forming
an ion pair with the nuclear receptor (the -NH 2 group decreases receptor affinity but
plays a role in transport of the hormones and delays their metabolic degradation). - A phenolic 4'-OH group, which may be generated metabolically (e.g.,by oxidation
in vivo) if originally absent. - A lipophilic halogen, alkyl, or aryl substituent in the 3' position. An isopropyl group
has the optimal effect. - A 5' substituent reduces activity in direct proportion to its size. It interferes with the
binding of the 4'-OH group, increases the binding to transport proteins, and there-
fore reduces the concentration of available free hormone.
5.19.1.4 Thyroid Agonists and Antagonists
Hypothyroidismcan occasionally be treated with a regular intake of iodide, but in the
case of non-functioning of the gland thyroxine must be used. Synthetic levothyroxine
is the preparation of choice.
The treatment of hyperthyroidismis less straightforward. Surgery, in the form of
thyroidectomy, is sometimes employed, although concomitant inadvertent removal of
the parathyroid glands may complicate the subsequent hormone treatments. Irradiation
with ingested^125 I 2 , primarily a γ-emitting isotope, or^131 I 2 ,a β-emitting isotope, is useful
because it destroys thyroid follicles selectively. While these methods offer advantages
over thyroidectomy, all of the dangers inherent in radioisotope treatment must be carefully
considered prior to their use. Alternatively, several pharmacologic agents can be used.
Goitrogens, or compounds that produce hypothyroidism (or preferably euthyroidism
[i.e., normal thyroid functioning] in a hyperthyroid individual), were recognized many
years ago. Of historical interest, some are naturally occurring, like progoitrin (5.108),
which is transformed into the cyclic compound goitrin (5.109) in rutabaga plants. Large
anions such as thiocyanate (SCN−), pertechnetate (TcO 4 −), or perchlorate (ClO 4 −) were
once used clinically (especially potassium perchlorate) as competitive inhibitors of iodide
362 MEDICINAL CHEMISTRY