The Benzodiazepine Binding Sites of GABAA Receptors

Multiple non-canonical sites of benzodiazepine actions including structurally non-homologous sites in the transmembrane domain have been described. Extrasynaptic GABAA receptors responsive to ligands of the benzodiazepine chemotype are valuable drug targets. Pharmacogenetic approaches lead to disentangling of the physiological function of individual receptor subunits. Negative allosteric modulators acting selectively at specific benzodiazepine binding sites may, contrary to expectations, represent useful drugs, as exemplified by basmisanil. Transgenic animals point the way towards potentially novel therapeutic indications of a new generation of benzodiazepines with improved selectivity. Optogenetic methods have started to be applied to GABAA receptor research and may contribute useful insights. Everyday activity is based on a subtle equilibrium of excitatory and inhibitory neuronal systems. The most prominent players in neuronal inhibition are synaptic and extrasynaptic GABAA receptors. Benzodiazepines are popular drugs that act as positive allosteric modulators of a subset of these receptors. Benzodiazepines have sedative, hypnotic, muscle-relaxant, and anticonvulsive effects, and are of outstandingly low overdose risk. The discovery of a large number of subtypes of GABAA receptors has raised hopes for a clear separation of this spectrum of actions. We discuss here how far this separation has been achieved, and outline recent progress towards the discovery of novel ligands for canonical and non-canonical binding sites. Everyday activity is based on a subtle equilibrium of excitatory and inhibitory neuronal systems. The most prominent players in neuronal inhibition are synaptic and extrasynaptic GABAA receptors. Benzodiazepines are popular drugs that act as positive allosteric modulators of a subset of these receptors. Benzodiazepines have sedative, hypnotic, muscle-relaxant, and anticonvulsive effects, and are of outstandingly low overdose risk. The discovery of a large number of subtypes of GABAA receptors has raised hopes for a clear separation of this spectrum of actions. We discuss here how far this separation has been achieved, and outline recent progress towards the discovery of novel ligands for canonical and non-canonical binding sites. a molecule that binds to a site distinct from that bound by agonists in proteins and that does not induce activity by itself, but modulates activity triggered by an agonist. a class of drugs that mainly affect the central nervous system. Classical benzodiazepines promote neuronal inhibition. a family of homologous receptors composed of subunits that contain a characteristic sequence flanked by two cysteine residues. one of the first benzodiazepines marketed under the name valium. γ-amino butyric acid, the major inhibitory neurotransmitter. This is in fact a misnomer because only very small amounts of the acid form of the neurotransmitter are present at physiological pH. a ligand-gated chloride-selective ion channel belonging to the cys-loop family of pentameric receptors. procedures carried out using computational methods. ligands of the high-affinity benzodiazepine site that have a non-benzodiazepine structure; examples include zolpidem, zaleplon, and zopiclone.