GABAA receptors as targets for different classes of drugs

Abstract

GABA A receptors are the major inhibitory transmitter receptors in the brain and are the site of action of many clinically important drugs that modulate anxiety, excitability of the brain, feeding and drinking behavior, circadian rhythms, cognition, vigilance, learning and memory. Evidence has accumulated for the existence of a multiplicity of GABA A receptor subtypes with distinct regional, cellular and subcellular distribution in the brain. Each of these receptors has a distinct structure and thus also exhibits distinct pharmacological properties. Drugs selectively interacting with these receptor subtypes should therefore exert highly selective actions. This conclusion was recently supported by evidence indicating that different receptor subtypes mediate different actions of drugs. This review discusses recent progress in the development of GABA A receptor subtype-selective drugs, as well as recent structural information indicating that these receptors contain a multiplicity of possible binding pockets that could become targets for the development of novel drugs with subtype-specific actions. Targeting drugs to GABA A receptor subtypes holds promise for the treatment of various diseases with a reduced incidence of side effects. In addition, therapeutic applications beyond those of classical benzodiazepines may emerge for drugs specifically enhancing or reducing the activity of minor GABA A receptor subtypes located only at certain neurons.