The primary effect of ACTH seems to be mediated via cAMP production by interaction
of the hormone with differing populations of receptors. The difference between the
extent of steroidogenesis and cAMP formation indicates different receptor affinities in
different organs.
Clinically, ACTH stimulation of the adrenals is used diagnostically to detect adrenal
insufficiency; plasma cortisol levels are measured before and 60 minutes following an
intravenous injection of cosyntropin. Adrenocortical insufficiency is known as Addison’s
disease; Addison’s classic description, in 1855, namely “general debility, remarkable
feebleness of the heart, irritability of the stomach, and a peculiar change of the colour
of the skin”, summarizes the clinical features of this disease, which is uniformly fatal
if undetected and untreated. Therapeutically, corticotropin therapy has been essentially
abandoned in favor of the direct administration of glucocorticoids. However, ACTH is
still rarely used in the treatment of the infantile spasm seizure disorder.
5.17 PEPTIDE HORMONES OF THE POSTERIOR PITUITARY
5.17.1 Oxytocin (OT)Oxytocin (OT) is a nonapeptide in which six amino acids form a ring closed by a disul-
fide bridge, while the ring itself forms an antiparallel “pleated sheet.” The “tail” portion
of the peptide, composed of Pro-Leu-Gly-NH 3 , is also rigidly held in a folded confor-
mation. Oxytocin causes the powerful contraction of some smooth muscles and plays a
vital role in milk ejection (not to be confused with milk secretion, which is regulated
by prolactin). It also has uterotonic action, contracting the muscles of the uterus, and is
therefore used clinically to induce childbirth.
5.17.2 Vasopressin (VP)Vasopressin occurs in two variations: arginine-vasopressin (AVP) and lysine-
vasopressin (LVP), in which Arg^8 is replaced by Lys. The conformation of these
hormones is almost identical to that of oxytocin, except that the terminal “tail” is con-
formationally free and not held by the ring. The physiological role of the vasopressins
is the regulation of water reabsorption in the renal tubules (i.e., an antidiuretic action).
In high doses, they promote the contraction of arterioles and capillaries and an increase
in blood pressure; hence the name of these hormones. Because of their very similar
structures, OT and VP overlap in a number of effects.
5.17.3 Structure–Activity Correlations of OT and VPThe elucidation of the conformation–activity relationships of OT was of the utmost
importance in the design of highly active analogs of these hormones. Amino acids 3, 4,
7, and 8 are not involved in the hydrogen bonding that determines the ring conforma-
tion, and can therefore act as sites of binding to the oxytocin receptor. The Tyr^2 -
hydroxyl group, the intact hexapeptide ring, and the amide of Asn^5 are essential for
the biological activity of this hormone. Therefore, the “corner” amino acids 3, 4, and
8 can be varied, yielding more selective compounds: the [Thr^4 ,Gly^7 ] OT has an
348 MEDICINAL CHEMISTRY