Medicinal Chemistry

imidazoles) and six-membered (pyrimidines, pyridines) heterocycles have been explored
as potential structural cores.
These various CRF-active agents may have clinical application in a variety of disorders.
Selective small-molecule CRF 1 antagonists have been shown to reverse anxiogenic
(anxiety-producing) effects in experimental models. Such compounds may be useful
in the treatment of anxiety and agitated depression. CRF 1 and CRF 2 antagonists may be
useful in the treatment of stress-induced gastrointestinal dysfunction and in other bowel
motility disorders such as irritable bowel syndrome. Such agents may also be useful in
treating stress-induced relapse of drug abuse as well as the anxiogenic behaviors that
occur during acute drug or alcohol withdrawal. Finally, CRF antagonists may be of value
in the clinical management of stress-related alterations in food intake and weight gain.

5.16 PEPTIDE HORMONES OF THE ANTERIOR PITUITARY

The pituitary is one of the most important endocrine organs. Hormones are produced by
both the posterior pituitary and the anterior pituitary; the posterior pituitary produces
oxytocinandvasopressin.The anterior pituitary is directly influenced by the hypothala-
mic hormones. The anterior pituitary hormones include:thyrotropin(TSH, which influ-
ences the ability of the thyroid gland to produce other hormones called iodothryonines);
corticotropin(ACTH, which influences the ability of the adrenal cortex to produce cor-
ticosteroids);lutropinandfollitropin(which influence the capacity of the ovary and testis
to produce estrogen, progestins and testosterone); somatotropin(growth hormone, mod-
ulating insulin and glucagon and influencing growth); prolactin(which influences the
mammary glands); and melanotropin(which affects skin pigmentation). A number of
these pituitary hormones are important to the medicinal chemistry of drug design.

5.16.1 Gonadotropins

The gonadotropins are produced by the anterior pituitary (adenohypophysis) and the
placenta. This group of glycoproteins (carbohydrate-containing proteins) includes the
following hormones:

1. Lutropin (LH, luteinizing hormone, which in the male is called interstitial cell-
   stimulating hormone, ICSH)


2. Follitropin (FSH, follicle-stimulating hormone)


3. Human chorionic gonadotropin (hCG)


4. Human menopausal gonadotropin (hMG)

These are very complex hormones, having molecular weights of around 28,000. The α
subunit consists of 89 amino acids; the βsubunit consists of 115 amino acids in LH and
FSH, and of 145 in hCG. While the αsubunits of all gonadotropins are very similar in
their amino acid sequence, the βsubunits of the various hormones are quite different.
The carbohydrate portions of both the α andβsubunits contain oligosaccharides
attached at specific amino acids (Asn), which branch at a mannose group and contain
galactose, glucosamine, galactosamine, and acetylneuraminic acid residues. The carbo-
hydrate portion of the hormones influences their biological and immunological proper-
ties as well as their stability.

346 MEDICINAL CHEMISTRY