Ea. Ertel et Cj. Cohen, VOLTAGE-DEPENDENT INTERACTIONS - THE INFLUENCE AND SIGNIFICANCE OF MEMBRANE-POTENTIAL ON DRUG-RECEPTOR INTERACTIONS, Drug development research, 33(3), 1994, pp. 203-213
Some major drugs exert their therapeutic effect by inhibiting currents
through voltage-gated ion channels. In particular, Na channels are bl
ocked by local anesthetics, Class I antiarrhythmics, and some anticonv
ulsants (phenytoin and carbamazepine) whereas Ca channels are blocked
by dihydropyridines (nifedipine), phenylalkylamines (verapamil), and b
enzothiazepines (diltiazem). Although their binding site is often pres
ent in many different tissues, most of these compounds have a good the
rapeutic index and are relatively tissue-specific in their action. Man
y such drugs have been studied in considerable detail and their mechan
isms of action were often found to be similar. In general, drug bindin
g is strongly modulated by the pattern of electrical activity associat
ed with the target channel and is most potent for patterns associated
with pathological conditions. The most widely held hypothesis suggests
that this happens because nearly all the therapeutically useful block
ers of voltage-gated ion channels have an allosteric interaction with
the gating mechanism oi the target channel, such that drug binding is
greatly favored by specific conformations of the channel. In this revi
ew, we describe the different models that have been proposed to accoun
t for time- and voltage-dependent block of Na and Ca channels, with pa
rticular emphasis on recent advances in our understanding of these phe
nomena. We also discuss the use of similar principles to describe the
action of channel activators and we suggest possible future directions
. (C) 1994 Wiley-Liss, Inc.