The Benzodiazepine Receptor

The 1,4-benzodiazepines have become the most frequently prescribed of all psychotropic drugs since the introduction of the first member of this series, chlordiazepoxide, into clinical practice in 1960. The compounds are used as anxiolytics, sedative/hypnotics, anticonvulsants, and muscle relaxants. This unique spectrum of activity, together with their large therapeutic index and essential lack of disturbing peripheral side effects, has assured their popularity and today over 25 analogs are available for prescription worldwide. Like many drug discoveries, that of the benzodiazepines owes much to serendipity (Sternbach, 1978). Chlordiazepoxide was originally thought to be a quinazoline-N-oxide (Fig. 1.1) and its subsequent pharmacological testing showed a novel activity profile, now uniquely associated with drugs of this chemical class. This in turn led to the synthesis of further analogs, and correction of the original structural assignment (Fig. 1.2). Structure-activity studies resulted in the synthesis of more potent compounds possessing the same activity profile and the second compound in the series, diazepam (Fig. 1.3), was introduced to the market in 1963. The first clues to the mechanism of action of the compounds came from electrophysiological studies with the observation by Schmidt et al. (1967) that diazepam increased primary afferent depolarization in the spinal cord. It is now clear that this was because of presynaptic inhibition, an event mediated by the inhibitory neurotransmitter y-aminobutyric acid (GABA) (see Levy, 1977). Since that time many other electrophysiological studies have shown that the benzodiazepines appear to facilitate GABAmediated transmission in many areas of the mammalian CNS; the phenomenon appears to be quite general for those events mediated through GABAA receptors (bicuculline-sensitive, baclofen-