Diabetes insipidus is treated with highly active synthetic vasopressin analogs.
Desmopressin acetate (5.79, DDAVP) is synthetic 1-desamino-8-D-arginine vasopressin
and is the synthetic vasopressin analog of choice for the treatment of diabetes insipidus.
Desmopressin may be given intranasally, intramuscularly, or intravenously. Lypressin
(5.80, 8-L-lysine vasopressin) and felypressin (5.81, 2-L-phenylalanine-8-L-lysine vaso-
pressin) are two other, less clinically successful, synthetic vasopressin analogs. These
synthetic agents have largely supplanted the use of pitressin (5.82), a sterile water extract
from the posterior pituitary of healthy domestic animals slaughtered at an abattoir.
In addition to the treatment of diabetes insipidus, vasopressin receptor modulators
may have utility in a variety of other disorders. Vasopressin interacts with at least three
G-protein-mediated receptor subtypes: V1a,V1b,and V 2. V1areceptors are located pre-
dominantly in vascular smooth muscle and blood platelets, contributing to vasoconstric-
tion and platelets aggregation; V1breceptors are in the anterior pituitary and influence the
release of ACTH and β-endorphin; V 2 receptors are localized in the kidney and regulate
a subset of transmembrane water channels, called aquaporin-2 channels. In accord with
this surprising diversity of receptor distribution, vasopressin modulators have been sug-
gested as therapeutics for a variety of common disease states. V 2 and V1a/V 2 mixed recep-
tor antagonists have been targeted for the treatment of congestive heart failure and
hypertension (congestive heart failure is a disorder in which the heart begins to fail as a
mechanical pump, resulting in both “forwards failure”, in which the heart fails to meet
the blood perfusion requirements of the body, and “backwards failure”, in which the
heart cannot cope with the influx of fluid that it receives, causing fluid to pool in either
the lungs [pulmonary edema] or the legs [peripheral edema]). V1areceptor antagonists
have been targeted for the treatment of dysmenorrhea (difficult and painful menstrua-
tion) and glaucoma (disease of the eye characterized by increased intraocular pressure
arising either from excess production or decreased drainage of the aqueous humor within
the eye). Vasopressin is a local neurotransmitter used by the hypothalamus and has also
been implicated in learning and memory. Work on the development of non-peptidic
receptor specific vasopressin mimics and blockers is an active area of research.
5.18 PEPTIDE HORMONES OF THE OPIATE SYSTEM
Relief from pain has been an age-old aspiration of humankind. Natural substances—
opium alkaloids from the latex of the poppy (Papaver somniferum, the “sleep-bringing
350 MEDICINAL CHEMISTRY