Medicinal Chemistry

releasing factor, and prolactin inhibiting factor. A number of these hypothalamic
hormones are important to the medicinal chemistry of drug design.

5.15.2.2 Thyroliberin

Thyroliberin (thyrotropin releasing hormone, TRH) was the first releasing factor to be
isolated and synthesized. It has the simple tripeptide structure of pyroGlu-His-Pro-NH 2.
The three rings on the peptide decrease the accessibility of the peptide bonds to hydrol-
ysis by proteolytic enzymes and account for some oral activity, which is rare among
peptide hormones. Nevertheless, the hormone is quickly inactivated in vivo. It is active
in picogram amounts and liberates 200–2000 times its own amount of thyrotropin (thy-
roid stimulating hormone, TSH). Interestingly, it also promotes the release of prolactin,
another pituitary hormone, even though there is a specific prolactin-releasing factor
(PRF) in the hypothalamus; however, prolactin can also be released by numerous other
substances.
There are indications that thyroliberin is neurotropic, acting as a neuromodulator or
transmitter in the brain and spinal cord, and that it exhibits antidepressant activity.
Agonist analogs of TRH have been synthesized, showing that the πelectron system and
the basic imidazole ring are necessary for activity: the N-formyl-Pro-Met-His-Pro-NH 2
(5.69) has 40% of the full activity of TRH but is resistant to serum inactivation. Some

HORMONES AND THEIR RECEPTORS 341

Figure 5.2 The Hypothalamic Pituitary Axis: The hypothalamus is part of the diencephalon
within the brain. The pituitary, although located within the skull, is more correctly a part of the
endocrine system than the nervous system. Together, the hypothalamus and pituitary form the
interface between the nervous system and endocrine system and exert control over the majority
of other hormone secreting organs. Releasing and inhibiting factors permit the hypothalamus to
control the pituitary. Pituitary hormones are released into the general circulation, affecting meta-
bolic function throughout the thorax and abdomen.