cardiac patients. These previous analogs are termed 1,4-benzodiazepines since the
two nitrogen atoms within the diazepine ring are situated in a 1–4 arrangement with two
carbon atoms between them; clobazam (4.185) is a 1,5-benzodiazepine, having its
nitrogens in a 1–5 arrangement with three carbons between them. Clobazam is now a
benzodiazepine of choice for epilepsy, with improved anticonvulsant activity in the
presence of decreased likelihood of tolerance developing to the anticonvulsant effects.
4.7.5.1 Mode of Benzodiazepine Action
The mode of action of benzodiazepines is apparently based on augmentation of
inhibitory neurons. The benzodiazepine receptor is an integral part of the GABAA
receptor, which is itself a chloride ion channel. From electrophysiological studies it is
known that these benzodiazepines increase the frequency of channel opening in
response to GABA. The resulting increased chloride conductance of the neuronal mem-
brane effectively short-circuits responses to depolarizing inputs. At the molecular level,
benzodiazepine receptor agonists increase the affinity of GABA to its receptor. Thus, at
a given concentration of GABA, binding to the receptors will be increased, causing an
augmented response and a corresponding diminution in excitability.
This mode of action imparts a variety of clinical uses upon the benzodiazepine class
of molecules. Probably first and foremost is their use as anxiolytics in the treatment of
anxiety disorders. In the context of psychiatric disorders, anxiety consists of apprehen-
sion, tension, and excessive concern over danger that is either minor in degree or largely
unrecognized; it is accompanied by signs of increased activity of the sympathetic ner-
vous system. Free-floating anxietyoccurs when there is no conscious recognition of a
specific external danger. Generalized anxiety disorderis characterized by the frequent
presence of excessive free-floating anxiety and overconcern, to the level that it inter-
feres with emotional comfort and effectiveness in living. Benzodiazepines are particu-
larly effective in the management of such disorders. Benzodiazepines are also quite
useful in the treatment of panic disorders (anxiety attacks associated with episodic fear-
fulness) and phobic disorders (anxiety attacks associated with intense fear of a situation
that the person consciously recognizes as harmless). Thus, while the antidopaminergics
(“major tranquilizers”) are useful for the treatment of major psychiatric disorders, the
benzodiazepines (“minor tranquilizers”) are the drugs of choice for minor psychiatric
disorders. Benzodiazepines have also found utility as anticonvulsants, sleep-inducing
agents, and general anesthetics.
4.7.5.2 Receptor Characterization and Drug Classification
Several receptors have been described for benzodiazepine agonists. The benzodiazepine
receptor is part of the GABAAprotein. As stated above, this protein is a pentamer com-
posed of combinations of structurally related subunit families (α,β,γ,δ,ρ), some of
which exist in multiple isoforms. The α-subunit bears the benzodiazepine (BDZ) binding
site. The Type I BDZ receptor, which displays high affinity for a wide range of benzo-
diazepine analogs, contains an α 1 subunit, whereas the Type II BDZ receptor, which has
a lower affinity for such agents, contains α 2 orα 3 subunits. Since an increasing number
276 MEDICINAL CHEMISTRY