Abstract
GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This pentameric structure not only allows different receptor binding sites, but also various types of ligands, such as orthosteric agonists and antagonists, positive and negative allosteric modulators, as well as second-order modulators and non-competitive channel blockers. A fact, that is also displayed by the variety of chemical structures found for both, synthetic as well as nature-derived GABA(A)-receptor modulators. This review covers the literature for natural GABA(A)-receptor modulators until the end of 2017 and discusses their structure-activity relationship.
Highlights
GABA (γ-aminobutyric acid) type A receptors are members of the ligand-gated ion-channel superfamily, consisting of four hydrophobic transmembrane domains (TM1–TM4) [1]
Despite the extensive heterogeneity of the GABA(A) receptor subunits, most GABA(A) receptors expressed in the brain consist of two α subunits, two β subunits and one γ subunit [1]
The receptor contains several different allosteric binding sites, which modulate the activity of the receptor indirectly and are the targets of various other drugs, such as benzodiazepines, barbiturates, ethanol, picrotoxin, general anaesthetics and neuroactive steroids [4,5,6,7]
Summary
GABA (γ-aminobutyric acid) type A receptors are members of the ligand-gated ion-channel superfamily, consisting of four hydrophobic transmembrane domains (TM1–TM4) [1]. Its endogenous ligand is GABA, the major inhibitory neurotransmitter in the central nervous system, which upon activation selectively conducts Cl− through its pore, resulting in hyperpolarization of the neuron [3]. This causes an inhibitory effect on the neurotransmission by diminishing the chance of a successful action potential occurring [3]. The receptor contains several different allosteric binding sites, which modulate the activity of the receptor indirectly and are the targets of various other drugs, such as benzodiazepines, barbiturates, ethanol, picrotoxin, general anaesthetics and neuroactive steroids [4,5,6,7]
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