GabaA types

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

Currently, the majority of all approved diugs for treating insomnia interact with the GABAa receptor system. The major focus of the rest of this overview will therefore be on these types of dtugs and the introduction of two novel approaches, either recently approved or in late stage development. 

Figure 11.7 Presumed arrangement of GABAa receptor subunits to form a receptor-channel complex, (a) Diagrammatic representation of an individual subunit with four transmembrane regions, extracellular sites for glycosylation and a site for phosphorylation on the intracellular loop between M3 and M4. (b) Association of five subunits to form a central ionophore bounded by the M2 region of each subunit. The suggested stoichiometry of the most widely expressed form of receptor is 2a, 2 and ly. Shown below are the possible subunit combinations of one such benzodiazepine-sensitive receptor together with a benzodiazepine-insensitive receptor in which the 7 subunit is replaced by a c5, and a ti-containing receptor with four different subunit types...

Shingai, R, Sutherland, ML and Barnard, EA (1991) Effects of subunit types of the cloned GABAa receptor on the response to a neurosteroid. Eur. J. Pharmacol. 206 77-80. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

As for the GABAa receptor, positive modulators that enhance glycine receptor activity have been identified. These include alcohols, neurosteroids, tropeines and the divalent metal ion Zn2+, which is highly enriched in some types of excitatory neuron [27], Zn2+ release from such neurons may potentiate glycine receptors at neighboring inhibitory synapses and thus facilitate inhibition following strong excitation. 

Brickley, S. G., Cull-Candy, S. G., and Farrant, M. (1999) Single-channel properties of synaptic and extrasynaptic GABAA receptors suggest differential targeting of receptor sub-types. J. Neurosci. 19,2960-2973. 

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