Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

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Abstract
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.