The Benzodiazepine Binding Sites of GABAA Receptors

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 GABA(A) 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 GABA(A) 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.