DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1130 important role in energy metabolism. The thyroid also
contains parafollicular cells (C-cells) that produce calcitonin
(Chapter 44).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
History. The thyroid is named for the Greek word for “shield
shaped,” from the shape of the nearby tracheal cartilage. It was first
recognized as an organ of importance when thyroid enlargement
was observed to be associated with changes in the eyes and the
heart in the condition we now call hyperthyroidism. Parry saw his
first patient in 1786 but did not publish his findings until 1825.
Graves reported the disorder in 1835 and Basedow in 1840.
Hypothyroidism was described later, in 1874, when Gull associated
atrophy of the gland with the symptoms characteristic of
hypothyroidism. The term myxedema was applied to the clinical
syndrome in 1878 by Ord in the belief that the characteristic thickening
of the subcutaneous tissues was due to excessive formation
of mucus. In 1891, Murray first treated a case of hypothyroidism by
injecting an extract of sheep thyroid gland, later shown to be fully
effective when given by mouth. The successful treatment of thyroid
deficiency by administering thyroid extract was an important step
toward modern endocrinology.
Extirpation experiments to elucidate the function of the thyroid
were at first misinterpreted because of the simultaneous removal
of the parathyroids. However, Gley’s research on the parathyroid
glands in the late 19th century allowed the functional differentiation
of these two endocrine glands. The structure of parathyroid hormone,
however, was not reported until the early 1970s. Calcitonin was discovered
in 1961, demonstrating that the thyroid gland produced a
hormone in addition to thyroxine.
Chemistry of Thyroid Hormones. The principal hormones of the
thyroid gland are the iodine-containing amino acid derivatives of
thyronine (T 4
and T 3
; Figure 39–1). Following the isolation and the
chemical identification of thyroxine, it was generally thought that
all the hormonal activity of thyroid tissue could be accounted for by
its content of thyroxine. However, careful studies revealed that crude
thyroid preparations possessed greater calorigenic activity than could
be accounted for by their thyroxine content. The presence of a “second”
thyroid hormone was debated, but triiodothyronine was finally
detected, isolated, and synthesized by Gross and Pitt-Rivers (1952).
Triiodothyronine has a much higher affinity for the nuclear thyroid
hormone receptor compared with thyroxine and is much more potent
biologically on a molar basis. The subsequent demonstration of T 3
production from T 4
in athyreotic humans led to the practice of effective
replacement in hypothyroidism with levothyroxine only
(Braverman et al., 1970).
Structure–Activity Relationships. The structural requirements for a
significant degree of thyroid hormone activity have been defined
(Baxter and Webb, 2009; Yoshihara et al., 2003). The 3′-monosubstituted
compounds are more active than the 3′,5′-disubstituted molecules.
Thus, triiodothyronine is five times more potent than thyroxine, and
3′-isopropyl-3,5-diiodothyronine has seven times the activity.
Substitutions at the 3,5,3′, and 5′ sites influence the conformation
of the molecule. In thyronine, the two rings are angulated at ~120°
at the ether oxygen and are free to rotate on their axes. As depicted
schematically in Figure 39–2, the 3,5 iodines restrict rotation of the
two rings, which tend to take up positions perpendicular to one
Figure 39–1. Thyronine, thyroid hormones, and precursors.
another. In general, the affinity of iodothyronines for the thyroid hormone
receptors (TRs) parallels their biological potency (Yen, 2001),
but additional factors can affect therapeutic potency, including affinity
for plasma proteins, rate of metabolism, and rate of entry into
cell nuclei. Specific thyroid hormone transporters, such as MCT8,
are likely to be important in specific tissues.
The stereochemical nature of the thyroid hormones plays an
important role in defining hormone activity. Many structural analogs
of thyroxine have been synthesized to define the structure–activity
relationship, to detect antagonists of thyroid hormones, and to find
compounds exhibiting a desirable activity while not showing
unwanted effects. Introduction of specific arylmethyl groups at
the 3′ position of triiodothyronine results in analogs that are liverselective,
cardiac-sparing thyromimetics (Brenta et al., 2007).
Solving the x-ray crystallographic structure of the ligand binding
domains of the nuclear thyroid hormone receptors α and β has
resulted in the rapid development of a range of TR isoform-selective
compounds. The difference in the ligand binding domain pocket
between TRα and TRβ is only a single amino acid (Ser 277 in TRα