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Web Box 18.4: Pharmacology in Action: GABAA Receptor Subunit-selective Drug Development

As you may recall from Chapter 8, the GABAA receptor is made up of five subunits that form a chloride channel (Figure 1). These subunits vary depending on brain region but a common combination of subunits is two α subunits, two β subunits and one γ. More recently it has been found that there are also multiple forms of each of the subunits. By understanding their localization in the brain and their function in modulating behavior, it is possible that new drugs may be developed that act selectively on GABAA receptors with distinct subunit isoforms, so that treatment of GABA-associated pathology including anxiety, seizures, sleep disorders, and memory deficits can be targeted with minimal side effects.

Figure 1  The GABAA receptor consists of five subunits that form a Cl-conducting channel. In addition to the GABA binding site on the receptor complex, there are additional modulatory sites for benzodiazepines, barbiturates, neurosteroids, and picrotoxin. Note that the locations of the various binding sites are depicted arbitrarily and are not meant to imply the actual locations of these sites on the receptor.

The most significant focus has been on the six forms of the alpha subunit (α1-6). Knockout mice with selective deletion of a particular α-subunit from the GABA receptor showed that without the α1 subunit, diazepam failed to produce sedation. Hence BDZ-induced sedation is mediated by the α1GABAA receptor. In contrast, α2 subunits mediate the anxiolytic effects of BDZs and GABAA receptors with the α5 subunit are apparently responsible for the cognitive and amnesic effects of the drugs.

There are a number of subunit-selective compounds available for research but only one subtype-selective drug is in clinical use. The sedative-hypnotic drugs zolpidem (Ambien) and zaleplon (Sonata) are not BDZs but bind to the BDZ modulatory site. They have a relatively selective affinity for GABA receptors having the α1 subunit. They are useful in the short-term treatment of insomnia, but have minimal anti-convulsant, muscle relaxant, or anti-anxiety effects except at high doses. Drugs effective in relieving anxiety without sedation as a side effect are in the development stage. Some of these include Ocinaplon, SL-651498, Pagoclone, MRK-409, R121919, and others. These drugs show anxiolytic effects in animal testing but produce muscle relaxation, sedation, and ataxia only at doses significantly higher than that needed for reduction of anxiety. TPA023 has been clinically tested in individuals with GAD in Phase II trials. As predicted by its receptor selectivity, the drug was more effective than placebo in relieving anxiety without significant sedation. Unfortunately because some individuals in long term studies developed cataracts, further development was discontinued (see Möhler, 2011). Nevertheless, this line of subunit selectivity clearly has promise. The GABAA receptors having the α5 subunit are densely located in the hippocampus and were shown to modulate hippocampal-dependent learning and memory. Results from animal studies have prompted investigation into the potential for enhancing memory for patients with Alzheimer’s disease and other dementias with drugs that act as inverse agonists at GABAA receptors having the α5 subunit. Since agonists at these receptors enhance GABA function and impair memory, it follows that an inverse agonist that binds to it and reduces the effectiveness of GABA should improve memory. In several studies, rodents showed improved performance in working memory and spatial memory tasks. Furthermore, because of the α5 subunit selectivity such memory enhancement was not accompanied by increased motor impairment, anxiety, or seizures. Results like these are encouraging, but significant issues in the development of these molecules, such as metabolic instability and pharmacokinetic properties as well as poor tolerability in healthy elderly volunteers has slowed the pace of development for further testing.

References

Möhler, H. (2011). The rise of a new GABA pharmacology. Neuropharmacol., 60, 1042–1049.

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