From a clinical perspective, some of these PCO classes have attracted initial attention.
Diazoxide and minoxidil have been evaluated as antihypertensive agents. These PCOs
open K+channels in the plasma membranes of vascular smooth muscle cells, causing
vascular vasodilation, thereby lowering blood pressure. Cromakalim has been investi-
gated as a smooth muscle bronchodilator for the treatment of human asthma. Nicorandil
was launched in Japan in 1984 for the treatment of angina because of its perceived ability
to promote vasodilation of coronary arteries. Developmental work on these and other PCOs
is continuing for indications ranging from hypertension, asthma, urinary incontinence,
psychosis, epilepsy, pain, and alopecia (hair loss).
7.4.6 Targeting the Calcium Channel Protein: AntagonistsThe adult human body contains about 1100 grams of calcium. The plasma concentra-
tion of Ca^2 +is normally about 2.5 mmol/L (5 mEq/L, 10 mg/dL). The Ca^2 +cation is
extremely important to the molecular processes of human physiology. Ca^2 +plays a
central role in the release of neurotransmitter molecules into the synaptic cleft during
messenger-based interneuronal communication. Transmembrane Ca^2 +flux is then itself
part of the neurotransmitter message when the transmitter receptor is linked to a ligand-
gated cation channel such as the NMDA channel. When the nervous system connects to
muscles, Ca^2 +is once again a crucial intermediate. Ca^2 +is a key player during the con-
traction of muscles, whether they are striatedmuscles (e.g.,skeletal musclein the arms
or legs, or cardiac musclewithin the heart) or smooth muscle(e.g., enabling constric-
tion of arteries). Within the endocrine system, various hormones (e.g., parathyroid hor-
mone, calcitonin) exert control over Ca^2 +homeostasis. Accordingly, Ca^2 +concentrations
influence cardiac function, affecting both muscle contractility and heart rate. When a
person breathes too fast (“overbreathing,” causing hyperventilation) the resulting reduc-
tion in arterial carbon dioxide concentration (hypocapnia) yields an elevation of blood
pH (respiratory alkalosis) which cause a concomitant reduction in plasma Ca^2 +levels
(hypocalcemia), producing a clinical phenomenon known as tetany; one of the hall-
marks of tetany is Trousseau’s sign, in which spasm of the hand and arm muscles causes
flexion of the wrist and thumb with extension of the fingers. Ca^2 +is also involved in
blood clotting, playing a role in the cascade or proteins that biosynthesize a blood clot.
Ca2+also plays a structural role in the inorganic chemistry of bone. Finally, during
pathological processes (such as ischemia, producing stroke or a heart attack) an influx
of Ca^2 +and an increase in intracellular Ca^2 +signals the so-called “final common pathway
leading to cellular death.”
424 MEDICINAL CHEMISTRY