differing bioactivities, most clinical studies have been done on racemic mixtures. The
optical isomers arise from the restricted conformational rotation around the single bond
connecting the two naphthalene ring systems.
5.11 STEROID HORMONES: ADRENOCORTICOIDS
(ADRENAL STEROIDS)—OVERVIEW
The adrenal gland is a cap-like organ sitting at the upper pole of the kidney.
Histologically, the gland consists of the inner adrenal medullaand the outer adrenal
cortex(shell). In accord with this histological differentiation, there are two endocrine
organs within the adrenal gland, one surrounding the other. The inner adrenal medulla
secretes the catecholamines: epinephrine and norepinephrine. The outer adrenal cortex
secretes corticosteroid hormones: glucocorticoids and mineralocorticoids. The adrenal
cortex is divided into three zones:zona glomerulosa(outer),zona fasciculata(middle),
andzona reticularis(inner). Although these three zones are variable in their anatomical
distinctness, they are definite in their biochemical distinctness. All three cortical zones
secrete corticosterone: the zona glomerulosa biosynthesizes aldosterone; the zona fas-
ciculate and zona reticularis biosynthesize cortisol (and sex hormones as well).
Like most endocrine glands, the adrenal cortex is regulated by hypothalamo-pituitary
peptides.The hypothalamus secretes corticotropin releasing factor(CRF) (see section
5.15.2.6), which controls the release of adrenocorticotropin(ACTH), a peptide con-
sisting of 39 amino acids. Corticotropin secretion is under feedback regulation by the
adrenal steroids, as well as being under the control of higher CNS centers; stress or epi-
nephrine can also increase corticosteroid production. Adrenocortical secretion is con-
trolled primarily by ACTH from the anterior pituitary, but mineralocorticoid secretion
is also subject to independent control by circulating factors, of which the most impor-
tant is angiotensin II.
On the basis of biochemical effects, the two groups of corticosteroids can be readily
distinguished:
- Glucocorticoids,which act on carbohydrate, fat, and protein metabolism
- Mineralocorticoids,which regulate electrolyte balance through Na+retention
Since these two classes of corticosteroids are both important in medicinal chemistry
and drug design, they will be discussed separately.
5.12 STEROID HORMONES:
ADRENOCORTICOIDS—GLUCOCORTICOIDS
Glucocorticoids have important metabolic effects on carbohydrates, proteins, and
lipids; they stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and
glycogen synthase. Glucocorticoids promote gluconeogenesis by increasing the pyru-
vate carboxylase concentration, and thus increase the concentration of oxaloacetate in
the mitochondrial pathway of pyruvate–phosphoenolpyruvate synthesis. Another effect
appears to be the inhibition of pyruvate oxidation. Glucocorticoids stimulate the release
of amino acids during the course of muscle catabolism. Glucocorticoids stimulate
332 MEDICINAL CHEMISTRY