Benzodiazepines were first synthesized in the 1930s but were not systematically evaluated until 20 years later. The introduction of chlorpromazine and meprobamate, which had sedative effects in animals, in the early 1950s, led to the decade of development of sophisticated in vivo pharmacological screening methods that were used to identify the sedative properties of benzodiazepines. More than 3,000 benzodiazepines have been synthesized since chlordiazepoxide, which was synthesized by Sterbach in 1957, was introduced into clinical medicine. About 40 of them are in clinical use.

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FIGURE 42–1. Chemical structures of some commonly used benzodiazepines.

FIGURE 42–2. The GABAA–benzodiazepine receptor complex.(A) Schematic model of the mammalian -aminobutyric acid type A (GABAA) receptor embedded in the cell membrane, representatively possessing the , , and subunits (2:2:1). The binding of two molecules of GABA to the action site composed of and subunits causes the opening of the chloride channel pore, and the chloride ions diffuse into the cell. Each subunit comprises four transmembrane domains (TM1–TM4). The ion channel pore consists of TM2 of five subunits with a rosette formation. (B) Structure of the 1 subunit, with amino acid sequence, indicating amino acid residues implicated in GABA and benzodiazepine binding domains.Source. Modified from Ueno et al. 2001.

FIGURE 42–3. Three nonbenzodiazepine hypnotics—zolpidem (an imidazopyridine), zopiclone (a cyclopyrrolone), and zaleplon (a pyrazolopyrimidine)—have been shown to be useful sedative-hypnotics with benzodiazepine-like profiles.

FIGURE 42–4. Properties of the various types of benzodiazepine receptor ligands.GABA = -aminobutyric acid.

FIGURE 42–5. Metabolic pathways for the principal 1,4-benzodiazepines.Solid and broken arrows denote major and minor pathways, respectively; commercially available drugs are underscored. Flurazepam, flunitrazepam, nitrazepam, and triazolam have separate metabolic pathways.

FIGURE 42–6. Duration of action of hypnotics and hangover and rebound insomnia.Hypnotics with long half-lives may impair daytime performance the day after drug administration, whereas short-acting compounds may induce rebound insomnia on discontinuation.
Table Reference Number
TABLE 42–1. Comparative properties of benzodiazepines and barbiturates on sleep parameters
Table Reference Number
TABLE 42–2. Pharmacokinetic properties of the most commonly used (in the United States) hypnotic compounds acting on the benzodiazepine receptors


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