Ligands of the GABAA Receptor Benzodiazepine Binding Site

Abstract

Benzodiazepine (BZ) binding site ligands are important central nervous system (CNS) drugs. Their numbers and our knowledge of how they interact with the BZ-binding site of GABAA receptors are both rapidly expanding. The GABAA receptor is a member of the ligand-gated ion channel superfamily. In general, it consists of an assembly of transmembrane pentamers of different subunit compositions (1). To date, at least 15 types of subunits (α1–6, β1–3, γ1–3, δ, e, and π) have been identified using molecular cloning techniques that combine in various combinations to give rise to the different GABAA-receptor subtypes (1–3). The central BZ-binding site is a part of the GABAA-receptor-associated chloride ion channel. Most functional subtypes of the GABAA receptor contain α, β, and γ subunits, with the different receptor subtypes displaying marked variations in their binding capacity to different BZ-binding site ligands (4,5). When GABA, the major inhibitory transmitter in the CNS, binds to a GABAA receptor, the chloride ion flux through the channel is increased. This leads to membrane hyperpolarization that results in a reduction in the excitability potential of the neuron (6). As a consequence, GABAA receptors are the molecular targets of a variety of pharmacologically and clinically important drugs, such as the anxiolytic, anticonvulsant, sedative-hypnotic benzodiazepines, some anxiogenic, convulsant β-carbolines, and the convulsants bicuculline or picrotoxinin. Furthermore, multiple recognition sites that exist within the three-dimensional structure of the various GABAA-receptor subtypes possess the capacity to interact with a host of different ligands (6). These sites include: the GABA site; the benzodiazepine site; the barbiturate site; the general anesthetic site; the picrotoxinin site; and the storage site for GABA. BZ-binding site ligands act through mechanisms