the slow entry of the resultant molecule into the CNS affects the onset of action.
Aromatic substituents produce anticonvulsant activity. Barbiturate enhancement of
GABA binding is proportional to the anesthetic activity of the barbiturate.
The principal disadvantages of barbiturates as hypnotics include the development of
physical dependence, a relatively low therapeutic index (and the potential of poisoning,
as in suicide), suppression of REM sleep, and possible hangover effects. As mentioned
above, benzodiazepines (e.g., flurazepam or brotizolam) are hypnotics as effective as
barbiturates and are much safer in terms of their therapeutic index, addiction potential,
and REM sleep-deprivation effects. Thus benzodiazepines have displaced barbiturates
as sedative hypnotics.
Like benzodiazepines, barbiturates bind to the GABAAreceptor—however, at a dif-
ferent site from the benzodiazepines. Measurements of mean ion channel open times
show that barbiturates act by increasing the proportion of channels opening to the longest
open state (i.e., 9 msec), resulting in an overall increase in Cl−flux into the neuron.
Figure 4.12 shows a schematic model of the GABAAchannel with representations of
benzodiazepine and barbiturate binding sites. There is also a binding site for neuro-
steroids, and analogs of such agents may emerge as useful anticonvulsants or general
anesthetics in future years.
278 MEDICINAL CHEMISTRY
Figure 4.12 The GABA-A channel functions as a receptor for many multiple different drug
classes, including benzodiazepines (e.g., diazepam) and barbiturates (e.g., phenobarbital). There is
also a steroid-binding site on the GABA-A channel which may be useful in the future design of
general anesthetics.