Subunit compositions of GABAA receptors determining the diversity of physiological processes and neurotropic properties of medicines

Abstract

Gamma-aminobutyric acid (GABA) became known as a potentially important chemical in the brain 50 years ago, but its significance as a neurotransmitter was fully found 16 years later. It is now known that at least 40 % of the inhibitory synaptic activity in the mammalian brain is accounted for by GABA. Аim. To analyze achievements in the study of the physiological and pharmacological role of GABA receptor subtypes, their potential applications in drug development and updated information on the clinical development of subtype-selective GABA receptor compounds. Results. The GABAA-receptor complex (GABA-RC) is ligand-gated ion channels with chloride conductance. These receptors contain α, β, and γ subunits, but δ, ε, θ, and ρ can be also present. The GABA binding site is located at the interface between α and β subunits where a number of important amino acids are also found. GABA-RC is sensitive to a wide range of drugs, e.g. benzodiazepines (BDZ), which are often used for their sedative/hypnotic and anxiolytic effects. Classical BDZ interact non-selectively with α1,3,5 βγ2 GABA-RС in the binding site located at the α+γ− interface. Conclusions. In addition to the potent and rapid pharmacotherapeutic action BDZ also possess some addictive potential (drug dependence), which appears after the interaction of molecules with α1-receptors. Using the selective targeting to separate subgroups not only the main effect of BDZ without side effects can be provided, but also one can use this approach in creating new analgesic medicines; we have demonstrated it on the example of propoxazepam (full agonist GABA-R).