Development of Subtype Selective GABAA Modulators: A Review Article
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GABAA receptors are Cl− channels that can be opened by GABA and are the major inhibitory neurotransmitter receptors in the Central Nervous System. A variety of pharmacologically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, general anesthetics and convulsants, produce at least part of their clinically relevant effects by interacting with distinct allosteric binding sites on GABAA receptors. GABAA receptors are involved in anxiety, feeding and drinking behavior, circadian rhythm, cognition, vigilance, and learning and memory. Different subtype mediates different functions. Neurons expressing α1GABAA receptors have been found to mediate sedation, whereas those expressing α2GABAA receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic α5GABAA receptors. In addition, neurons expressing α3GABAA receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. The phenotypic analysis of transgenic knock-in and knock-out mice in which particular GABAA receptors were rendered insensitive to the effects of BZ while others were unaffected confirmed this speculation. Subsequently, subtype-specific GABAA ligands were developed that, for example, retained the anxiolytic effects of BZs but were devoid of their sedative effects. Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drug.
α, β, γ Subunits, GABAA Receptors, benzodiazepine, diazepam, anxiolytic Abbreviations usedBZ, benzodiazepine, GABA, γ-aminobutyric acid; GABAA, GABA Type A.