Benzodiazepines

The benzodiazepines exert their effects through allosteric interactions at the γ-aminobutyric acid type A (GABA_A) receptor. GABA_A receptors are pentameric ligand-gated ion channels, and stimulation of these receptors by GABA leads to the influx of Cl^– and a resultant hyperpolarization of the postsynaptic cell (see Chapter 1). This hyperpolarization renders the cell less likely to fire in response to an incoming excitatory stimulus, thus mediating the inhibitory effects of GABA throughout the central nervous system (CNS).

GABA_A receptors contain primary agonist binding sites for GABA and multiple allosteric sites that can be occupied by numerous pharmacological compounds, as depicted in Figure 31-1. Benzodiazepines bind to one of these modulatory sites, often referred to as the benzodiazepine binding site or benzodiazepine receptor, whereas compounds such as the barbiturates and the poison picrotoxin bind to other sites on the receptor. When benzodiazepines bind to the benzodiazepine binding site, they induce a conformational change in the receptor, resulting in an increased frequency of chloride ion channel opening upon stimulation of the receptor by GABA. They are referred to as positive allosteric modulators because they increase the effect of the natural agonist but have no effect in the absence of agonist.

FIGURE 31–1 The GABA_A receptor depicting the membrane-associated protein composed of five subunits, the Cl^— channel, and relative location of binding sites for GABA, benzodiazepines, barbiturates, and picrotoxin.

Benzodiazepines are not the only group of compounds that bind to this allosteric site. The β-carbolines such as harmine and harmaline also interact with this site. However, when these compounds bind, they allosterically reduce Cl^– conductance by decreasing the affinity of GABA for its binding site. Because the β-carbolines increase CNS excitability and may produce anxiety and precipitate panic attacks, effects opposite to those of the benzodiazepines, they are called inverse agonists (see Chapter 1). The inverse agonists block the effects of the benzodiazepines but have no therapeutic use. However, they are found in nature and are thought to be responsible for the psychedelic properties of some plant species.

Benzodiazepine Antagonist

Flumazenil is a competitive antagonist that binds to the benzodiazepine site on the GABA_A receptor. As a competitive antagonist, flumazenil occupies the benzodiazepine site with high affinity but does not have the ability to activate it and does not affect GABA-mediated chloride ion influx. Rather, flumazenil competitively antagonizes the actions of the benzodiazepines and is used therapeutically to treat benzodiazepine overdose. Flumazenil also competitively antagonizes the effects of the inverse agonists and the benzodiazepine receptor agonists, because they also bind at the same allosteric site.

Non-Benzodiazepine Anxiolytics

Benzodiazepine Receptor Agonists

The benzodiazepine receptor agonists eszopiclone, zaleplon, and zolpidem, which are used to treat insomnia, are chemically unrelated to the benzodiazepines but bind to the same site as the benzodiazepines on the GABA_A receptor. However, in contrast to the benzodiazepines, which bind to all GABA_A receptors irrespective of their subunit composition, the benzodiazepine agonists bind only to a subset of GABA_A receptors containing a specific subunit composition. Thus these compounds have a different pharmacological profile than the benzodiazepines (see Relationship of Mechanisms of Action to Clinical Response). A summary of the mechanisms of action of compounds affecting the GABA_A receptor is presented in Table 31-1.

TABLE 31–1 Agents Affecting the GABA_A Receptor

Melatonin Receptor Agonists

Ramelteon is the first and only melatonin receptor agonist approved for the treatment of insomnia characterized by difficulty falling asleep. Ramelteon, like the hormone melatonin, has high affinity for both melatonin type 1 (MT₁) and type 2 (MT₂) receptors, both of which are G-protein coupled receptors. MT₁ and MT₂ are expressed throughout the brain and highly abundant in the suprachiasmatic nucleus of the hypothalamus, an area that is intimately involved in regulating circadian rhythms and sleep and is often referred to as the circadian pacemaker or “master clock.” As a pacemaker, the suprachiasmatic nucleus exhibits an intrinsic rhythm of activity that is inhibited at night as a consequence of the release of melatonin from the pineal gland. Studies suggest that ramelteon, like melatonin, activates melatonin receptors to inhibit the activity of the suprachiasmatic nucleus, leading to the induction of sleep.