Medicinal Chemistry

(Jacob Rumans) #1

to Lys^9 and Lys^15. The 4'-OH is a requirement for binding, which shows negative
cooperativity. It is interesting that, in addition to T 4 , four molecules of the small retinol-
binding protein, the vitamin A carrier, are also bound to TBPA. Serum albuminalso
transports T 4 , but with a KDof only 10−^6 M. In addition, there is a small amount of free
T 3 and T 4 in the serum (about 2 μg/L).


5.19.1.1 Biological Effects


The biological effects of iodothyronines are numerous:



  1. These hormones induce amphibian metamorphosis,the change of a tadpole into a
    frog—an obviously very complex series of biochemical and developmental reac-
    tions. Human fetuses will show skeletal abnormalities as well as neuromuscular and
    mental retardation if born with an inadequately functioning thyroid gland.

  2. Thyroid deficiency (hypothroidism) has been connected to cretinism and
    myxedema. Cretinism occurs when hypothyroid children are born intellectually
    handicapped, are small, and have coarse hair and thick skin. Myxedema, seen in
    older hypothyroid people, is characterized by subcutaneous semifluid deposits,
    causing puffiness of the hands and face. The basal metabolism of these patients is
    depressed to 30–40% below normal, and their body temperature and pulse rate are
    also reduced. Women suffering from hypothyroidism may give birth to children
    afflicted with cretinism.

  3. In hyperthyroidism the metabolic rate is increased, resulting in vasodilatation and
    sweating, weight loss, cardiac arrhythmias, diarrhea, and agitation. When the thy-
    roid gland enlarges as a result of increased activity, a goiter may develop. In certain
    geographical locations, this can be caused by a chronic lack of iodide; therefore
    iodized table salt is widely used throughout the world. In addition, hyperthyroidism
    may result in exophthalmos, in which the eyeballs protrude markedly. This probably
    occurs through an autoimmune process (Grave’s disease, the most common cause of
    hyperthyroidism), and can be very persistent even after hyperthyroidism is cured.
    The increased metabolic rate in the disease manifests itself as an increase in the
    oxygen demand of all tissue, except those of the brain, and an increased sensitivity
    toβ-adrenergic agonists.


5.19.1.2 Mode of Action


The mode of action of the iodothyronines is the regulation of protein synthesis in the
nuclei of cells sensitive to these hormones. The T 4 and T 3 hormones dissociate from
the thyroid binding proteins and enter the cell, probably by passive diffusion. Within the
cell the T 4 is metabolized to T 3 by 5'-deiodinase; the T 3 then enters the nucleus and
binds to a specific T 3 receptor protein. A nuclear receptor for thyroid hormones has been
isolated, showing a KDforT 3 on the order of 10−^9 –10−^10 M in many cell types. It is a
nonbasic, nonhistone protein associated with nuclear DNA and involved in regulating
the transcription of mRNA for a presumably large number of enzymes. This protein has
been isolated and cloned, and the nature of the T 3 binding pocket has been character-
ized. The receptor belongs to a family of receptors that are homologous with the


HORMONES AND THEIR RECEPTORS 361
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