physiology provide drug designers with ample opportunities for interference with these
processes.
A final interesting facet concerning neuropeptides/neurohormones concerns the exis-
tence of a family of “gut–brain” neuropeptide receptors. As numerous researchers have
observed, the gut seemingly has almost as much neuronal activity going on as the brain.
Peptides that function as either neurotransmitters or neurohormones within the CNS
may exhibit similar properties in the gut. For example, receptors for calcitonin, vasoac-
tive intestinal peptide, parathyroid hormone, secretin, glucagon, and growth hormone
releasing factor are found both in the brain and in the gut. The representation of such
receptors in both brain and gut must be considered during the drug design process, in
which organ-specific delivery of the drug molecule is a desired therapeutic end-point.
5.15.2 Peptide Hormones of the Brain: Hypothalamic NeurohormonesThe hypothalamus is located in the diencephalon in the upper portion of the brain stem.
Parts of the hypothalamus produce a number of hormonal peptides that are distributed
by the circulation (via the portal vein) and reach the pituitary gland (or hypophysis), sit-
uated immediately below the hypothalamus. The pituitary, unlike the hypothalamus, is
not part of the CNS because it lies outside the blood–brain barrier. The hypothalamic
peptides are hormones, but since they are secreted by neurons they can also be consid-
ered neurotransmitters, and some even fulfill the role of true neurotransmitters.
Additionally, these hypothalamic hormones regulate the synthesis and release of other
peptide hormones produced by the pituitary, and are thus called releasing hormones
(“releasing factors” or “inhibitory factors”, as the case may be). The release of these
hypothalamic neurohormones is regulated by higher brain centers through cholinergic,
dopaminergic, and GABAergic intervention; their synthesis is adjusted by feedback
mechanisms from the target organs.
The correlation of the hypothalamus and its hormones with the hormones of the ante-
rior pituitary gland is summarized in figure 5.2. There is no direct vascular connection
between the hypothalamus and the posterior lobe of the pituitary that would correspond
to the portal vein system for the anterior lobe of the gland. Not all hypothalamo-pituitary
hormones will be discussed in the subsequent sections. Only those that are well-defined
chemical entities or have a direct connection with drug action are considered.
5.15.2.1 Hypothalamic Releasing Factors
These peptides were isolated and their structure was elucidated primarily in the labora-
tories of Andrew Schally and Roger Guillemin, who shared the Nobel Prize in medicine
for this work in 1977. Since the early 1970s neuroendocrinology has undergone an
explosive development as a result. These hormones have an extremely high binding
affinity, with a KDranging from 2 to 20 × 10 −^10 M. They act on the plasma membrane
receptors of pituitary cells, triggering an energy-requiring process that probably
involves Ca^2 +and cAMP. Brain cell membranes also show the presence of receptors for
these hormones, as would be expected in a system regulated by feedback. The hypo-
thalamic hormones consist of thyroliberin, corticoliberin, gonadoliberin, melano-
liberin, somatocrinin (growth hormone releasing factor), somatostatin, prolactin
340 MEDICINAL CHEMISTRY