Clearly, Ca^2 + is an important regulator and mediator of endogenous molecular
processes, both functionally and structurally. Thus, from the perspective of a medicinal
chemist, Ca^2 +metabolism would seem to be an ideal target for pharmacological manip-
ulation. However, the fact that Ca^2 +is involved in so many processes likewise means
that drugs that influence calcium also run a substantial risk of producing side effects.
Since ion channels are the proteins that transport Ca^2 +across cell membranes, they are
the logical initial targets for drug design. The task of the drug designer is aided by the
fact that there are many types of calcium channel. Currently, four principal types of
voltage-gated calcium channel are recognized:
- L-type Ca^2 +channel (in muscles and neurons)
- N-type Ca^2 +channel (in brain)
- T-type Ca^2 +channel (in neurons and cardiac cells)
- P-type Ca^2 +channel (in cerebellar Purkinje neurons)
Each type of channel is a unique protein which, in principle, could be uniquely targeted
for purposes of drug design. Q- and R-type channels have also been described on the
basis of polypeptide toxin binding studies, but have not been extensively exploited for
purposes of drug design.
The L-type channel is the dominant one in cardiac and smooth muscle. As will be
discussed below, many classes of drug work at the level of this channel. Drug design
targeting the L-type channel has successfully created many clinically useful chemical
entities as therapeutics. The T-type channel also has potential clinical utility, but drug
design targeting this channel has been substantially less successful. Within the heart,
T-type channels are found, especially in the sinoatrial and atrioventricular nodes, which
are responsible for the generation and transmission of the electrical impulse that
establishes the heart beat. Mibefradil (7.33) is a combined T-type, L-type blocker (with
T-type specificity) that was developed for cardiovascular indications but was with-
drawn from continued clinical development because of cardiac toxicity and its numerous
interactions with other drugs, arising from inhibition of cytochrome P-450 dependent
enzymes. Certain anticonvulsant drugs, such as valproic acid (7.34) and ethosuximide
(7.35), seem to work specifically against primary generalized absence seizures by block-
ade of T-type channels within the thalamic region of the brain. Flunarizine (7.36), a weak
T-type blocker (initially developed as an H1-antihistamine), is an antimigraine agent
with some activity against seizures. N-type channels are a logical target for drug design
because of their role in neurotransmitter release. Naturally occurring toxins, such as
ω-CTX-GVIA, a conotoxin extracted from several marine snails of the genus Conus,
are selective antagonists of the N-type channel. Attempts to develop clinically useful
peptidomimetic agents based on these peptide toxins are an active area of drug develop.
For example, in 2005, zinconotide, an N-type Ca^2 +channel antagonist began to be used
clinically for the treatment of severe, refractory, chronic pain. The P-type channel is
blocked by Aga-IVA, a toxin of the funnel web spider,Agelenopsis aperta. Clinical utility
of P-type antagonists is less apparent.
L-type channel antagonists are the best developed and have been exploited for four
primary clinical indications, including:
ENDOGENOUS CELLULAR STRUCTURES 425