5.15.2.5 Somatostatin
Somatostatin (SS, growth hormone release-inhibiting hormone, GH-RIH) is perhaps
the best investigated and most important of the inhibitory factors produced by the
hypothalamus. It is a cyclic tetradecapeptide isolated by the Guillemin group in 1973.
It can be routinely produced by methods of genetic engineering that incorporate the
human somatostatin gene into the genome of Escherichia coli, providing an inexpen-
sive and efficient source of the hormone.
Somatostatin is very active at nanomolar levels, but is also very labile, and shows a
half-life of only a few minutes when injected. It is hydrolyzed by endopeptidases
between the Trp^8 -Lys^9 residues, and the therapeutic applications of the native hormone
are therefore rather restricted.
The principal activity of somatostatin is inhibition of the release of growth hormone
(somatotropin) from the pituitary. Excessive growth hormone production leads to
acromegaly, a form of gigantism, whereas its lack results in dwarfism. Since acromegaly
is a relatively rare endocrine disease, other actions of somatostatin have received more
attention—primarily its action on the pancreas. Somatostatin suppresses the release of
the pancreatic hormones insulin and glucagon. According to present views,diabetes
(more properly referred to as diabetes mellitusto distinguish it from diabetes insipidus)
is a common endocrine disease caused by lack of insulin and a loss of insulin receptors—
as well as a relative excess of glucagons—and causes hyperglycemia (an excessive blood
glucose concentration), faulty glucose metabolism, lipolysis, and amino acid mobiliza-
tion from proteins. In turn, this produces a number of chronic pathological effects includ-
ing blindness, neuropathy, and accelerated atherosclerosis. The contemporary treatment
of diabetes mellitus concentrates on the replacement of insulin or the administration of
nonpeptidic hypoglycemic drugs. It is conceivable that administration of supplementary
somatostatin (or of analogs thereof) to decrease the release of glucagon may also be used
to favorably influence glucose metabolism. Since obesity is becoming an epidemic dis-
order, especially in North America, diabetes mellitus is likewise anticipated to achieve
epidemic rates of occurrence in future years.
Somatostatin also reduces gastric acid secretion and has potential use in treating
gastric ulcers. Additionally, being distributed throughout the CNS, mainly in the spinal
cord, and found in nerve endings, it is assumed to be a neurotransmitter. It potentiates
some of the effects of L-DOPA, induces sedation and hypothermia, and affects sleep
patterns by inhibiting central epinephrine secretion. The suspected CNS targets include
the extrapyramidal motor system and perhaps cognition.
In view of the many actions of somatostatin that potentially have great therapeutic
importance, a very large number of synthetic analogs have been prepared, with partic-
ular attention being given to overcoming the impracticably short half-life of the native
hormone.
Modifications designed to enhance the enzyme resistance and prolong the activity of SS
derivatives have been quite successful. The use of D-amino acids instead of the normal
L-enantiomers (e.g., in Trp^8 ), or replacement of the disulfide link by a nonreducible
ethylene bridge, leads to an increased duration of activity, approaching 3 hours. Several
analogs show a greatly increased effect, like the [D-Ala^2 , D-Trp^8 ]somatostatin, which
has 20 times the activity of SS on growth hormone release. The NH-terminal outside the
cyclic dodecapeptide is not essential for activity. Selectivity of action results from
344 MEDICINAL CHEMISTRY