GABAA/Bz Receptor Subtypes as Targets for Selective Drugs

Abstract

The gamma-aminobutyric acid type A (GABA(A)) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride flux into the cell with subsequent hyperpolarization. Several GABA(A) receptor subunit isoforms have been cloned, the major isoform containing alpha, beta, and gamma subunits, and a regional heterogeneity associated with distinct physiological effects has been suggested. As a variety of allosteric ligands can modulate GABA-gated conductance changes through binding to distinct sites, the development of subtype-selective ligands may lead to the selective treatment of GABA system-associated pathology. In particular, the best characterized binding site is the benzodiazepine site (BzR), localized at the alpha/gamma subunit interface, in which the alpha subunit is the main determinant of BzR ligand action selectivity. The alpha1-containing BzR have been proposed to be responsible for the sedative action; the alpha2 and/or the alpha3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the alpha5 subtype has been associated with cognition processes. The discovery of alpha-selective subtype ligands may help in the specific treatment of anxiety, sleep disorders, convulsions and memory deficits with fewer side effects. Selectivity may be achieved by two approaches: selective affinity or selective efficacy. Selective affinity needs a compound to bind with a higher affinity to one receptor subtype compared with another, whereas subtype-selective efficacy relies on a compound binding to all subtypes, but having different efficacies at various subtypes. The status of BzR ligands, subdivided on the basis of their main chemical structural features, is reviewed in relation to structure-activity relationships which determine their affinity or efficacy selectivity for a certain BzR subtype.

Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats

“…Activation of these GBRs may produce sedative-like effects and anxiolysis (Da Settimo et al 2007). In addition to binding to ERβ, 3α-diol also binds to GBRs to produce anxiolytic-like effects (Gee 1988).…”

Population Patch-Clamp Electrophysiology Analysis of Recombinant GABAA α1β3γ2 Channels Expressed in HEK-293 Cells

“…It is generally accepted that the beneficial anxiolytic, myorelaxant, and cognitive effects of BDZs are mediated by α2 and α3 containing channels, whereas the undesirable sedative and dependence actions are α1 mediated. [7][8][9][10] There have been widespread and extensive searches for improved, subtype-selective drugs for GABA channels, but these have been hampered by the availability of suitable highthroughput screening (HTS) and secondary hit confirmation approaches (for review, see Smith and Simpson 11 ). Radioligand binding assays (e.g., 3 H flunitrazepam, 3 H muscimol) have proven useful but cannot differentiate agonism/ antagonism or positive/negative modulation and, with the multitude of recognition sites, fail to provide the full picture.…”

Structural and electronic effects of the C2’ substituent in 1,4–benzodiazepines

“…Since the model refers to the α1β2γ2 sub-type whose main effects are sedation, ataxia and anterograde amnesia [11,12] drugs belonging to G1, with exception of 1.a, presents more pronounced effects on sedation [9] and sideeffects as hypnotic, anxiolitic and myorelaxants. In fact, with regard to their primary pharmacological action diazepam 1.a has a markedly anxiolytic action, being a full agonist of BZs receptors, while flurazepam 1.b has a hypnotic action [25,26].…”

“…To facilitate this molecular design process, knowledge of the structural features and physical chemical characteristics of actual active drugs are essential. Also, the knowledge of the electronic and structural features of BZs may help on the understanding the affinity of BZs to specific subtypes of GABAA receptors [8][9][10][11][12], thus helping on the systematization of their main therapeutic activities.…”