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  • Review Article
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Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

Key Points

  • GABAA (γ-aminobutyric acid, type A) receptors are a family of ligand gated channels that regulate central nervous system function. GABAA receptor subtypes are formed by co-assembly from 19 different subunits (α1−6, β1−3, γ1−3, δ, ɛ, π,θ and ρ1–3) in a pentameric structure.

  • Genetic approaches and the development of GABAA receptor subtype-selective ligands have led to the identification of separable key functions of GABAA receptor subtypes.

  • GABAA receptor subtypes containing the α1, α2, α3 or α5 subunit, but not those containing the α4 or α6 subunit are sensitive to benzodiazepines, which modulate GABAA receptor function.

  • In addition to their anxiolytic effect, which is mediated by α2- and potentially also by α3-containing GABAA receptors, benzodiazepines possess sedative properties that are mediated by α1-containing GABAA receptors.

  • GABAA receptor subtype-selective compounds might be valuable for novel indications such as analgesia, depression, schizophrenia, cognitive impairment and stroke.

  • The most advanced compounds are currently being evaluated in clinical studies for anxiolytic and memory-enhancing effects; these compounds target α2- and α3-containing GABAA receptors (positive allosteric modulation) and α5-subunit containing GABAA receptors (negative allosteric modulation), respectively, and avoid functional effects at α1-containing GABAA receptors.

Abstract

GABAA (γ-aminobutyric acid, type A) receptors are a family of ligand-gated ion channels that are essential for the regulation of central nervous system function. Benzodiazepines — which non-selectively target GABAA receptors containing the α1, α2, α3 or α5 subunits — have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of insomnia and anxiety disorders. However, their use is limited by side effects and the risk of drug dependence. In the past decade, the identification of separable key functions of GABAA receptor subtypes suggests that receptor subtype-selective compounds could overcome the limitations of classical benzodiazepines; furthermore, they might be valuable for novel indications such as chronic pain, depression, schizophrenia, cognitive enhancement and stroke.

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Figure 1: Pharmacological effects and distribution of GABAA receptor α subunits in the mouse brain.
Figure 2: Structures of allosteric GABAA receptor modulators.
Figure 3: GABA-evoked currents in human embryonic kidney 293 cells.
Figure 4: GABAA receptor subtypes in the mesolimbic dopaminergic systems involved in addiction.

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Acknowledgements

Research by U.R. is supported by the National Institutes of Health (award numbers GM086448, MH080006, MH085149, DA027051, DA026578 and MH087829). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, the National Institute of Mental Health and the National Institute on Drug Abuse, or the National Institutes of Health. The authors gratefully thank T. Ballard-Yardy, R. Gasser, M.-C. Hernandez, A. W. Thomas and G. Trube (all at Roche Basel) for discussions, ideas and support.

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Correspondence to Uwe Rudolph.

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Uwe Rudolph is a full-time employee of McLean Hospital and a consultant for Sunovion. Frédéric Knoflach is a full-time employee of Roche.

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Glossary

Anterograde amnesia

Loss of memory for events occurring subsequent to the administration of a drug while memories from before the administration remain intact.

Ligand-gated chloride channels

Transmembrane proteins that open their channel pore in response to the binding of an appropriate ligand. The resulting influx of chloride through the opened pore results in hyperpolarization.

Allosteric modulation

This is achieved by a drug binding at a site distinct from the site required for activation of a protein. Positive allosteric modulation, which is also referred to as agonism, occurs when the binding of the drug enhances the activity of the protein. By contrast, negative allosteric modulation, which is also referred to as inverse agonism, reduces its activity.

Antihyperalgesic

A compound that reduces an increased sensitivity to noxious stimuli.

Nocifensive

Defensive response to pain.

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Rudolph, U., Knoflach, F. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov 10, 685–697 (2011). https://doi.org/10.1038/nrd3502

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