hormone-sensitive lipase and thus lipolysis. By promoting the supply of glucose from
gluconeogenesis, inhibiting peripheral glucose uptake, stimulating lipolysis, and releasing
amino acids from muscle catabolism, glucocorticoids ensure the supply of glucose to
the brain, especially in times of fasting or starvation. As do all steroids, glucocorticoids
increase the rate of enzyme synthesis in the nucleus of target cells and achieve their
effect on overall protein/enzyme synthesis in this manner. The principal target of gluco-
corticoids is the liver, although other organs—notably the muscles and brain—are also
rich in glucocorticoid receptors.
Most glucocorticoids have some mineralocorticoid effect, which is usually consid-
ered an undesirable activity. Through structural chemistry and structure–activity rela-
tionship (SAR) studies, molecular modifications can separate the two activities.
Glucocorticoids provide a valuable lesson in drug design. Since they influence so many
enzymes in so many cell types, the pharmacological effects of glucocorticoids are like-
wise many and far reaching. However, so too are their side effects. If the drug designer is
targeting a receptor that has widespread distribution and is not localized to a single tissue
or cell type, the likelihood of unwanted side effects is concomitantly increased.
5.12.1 Glucocorticoid ReceptorThe glucocorticoid receptor protein belongs to a superfamily of nuclear receptor pro-
teins that includes steroid, Vitamin D, thyroid, retinoic acid, and other receptors that
interact with promoters that regulate the transcription of target genes. Although the
glucocorticoid receptor differs from the estrogen or progesterone receptors, the basic
principles of its action seem to be the same. The glucocorticoid receptor is 800 amino
acids in length and has three functional domains: the C-terminal has the glucocorticoid
binding region, the middle portion has the DNA binding region (containing nine
cysteine residues folded into a “two finger” structure stabilized by Zn^2 +ions), and the
N-terminal, which has the receptor-specific region. A gene for the classic glucocorti-
coid receptor has been identified. Binding to the glucocorticoid receptor is somewhat
dependent on temperature, being optimal at 37°C.
Within the blood, the glucocorticoid steroid is bound to corticosteroid binding glob-
ulin (CBG); however, the steroid molecule enters the cell in an unbound state. Upon
entering the cell, it binds to the glucocorticoid receptor, which is itself bound to two
stabilizing proteins, including two molecules of heat shock protein (Hsp90). When the
steroid binds, the complex becomes unstable and the Hsp90 molecules are released. The
steroid–receptor complex is now able to enter the nucleus within the cell as an activated
dimer. The complex then binds to a glucocorticoid response element (GRE) on a gene
within the nucleus, thereby permitting regulation of transcription by the RNA poly-
merase II enzyme.
5.12.2 Glucocorticoids: Structure–Activity CorrelationsThe structure–activity relationships of glucocorticoids are based on two natural hormones,
cortisol (3.8) and corticosterone (5.61). The characteristic structural features of these
hormones are the conjugated 3-ketone, the 11-OH group, and the l7β-ketol side chain.
Molecular modifications have been aimed at deriving compounds with glucocorticoid
HORMONES AND THEIR RECEPTORS 333