α-Subunit selective modulators of GABA_A receptor function as CNS therapeutics

Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the CNS. Many drugs, including the benzodiazepines, exert their effects by modulating the GABA_A receptor complex, but side effects are common and reflect, in part, poor subunit selectivity. The subunits are arranged into heteropentamers and this produces a rich diversity of GABA_A receptor subtypes, which are potential targets for treating a variety of CNS disorders including epilepsy, anxiety and insomnia, as well as for ameliorating deficiencies arising from neurodegeneration, such as cognitive impairment. The identification of new ligands with improved subunit selectivity should reduce or abolish some of the side effects observed with current drugs, such as tolerance, dependence and withdrawal. This article focuses on new ligands that are reported to selectively recognise particular α-subunits of GABA_A receptors and may thereby offer improved treatments for CNS disorders. Only patents and literature since 1998 are necessarily included, although some earlier reports and reviews are also cited. Several publications and patent applications since 1998 disclose new compounds that modulate GABA_A receptor function without mentioning whether they have α-subunit selectivity; these compounds, like those known to interact with sites on other GABA_A subunits (particularly β), are not within the scope of this review.

• α-subunit
• γ-aminobutyric acid _A(GABA_A) receptors
• anticonvulsant
• anxiolytic
• benzodiazepine
• CNS
• cognition
• hypnotic
• sedative