Phenolics as GABA_A Receptor Ligands: An Updated Review

Natural products can act as potential GABA modulators, avoiding the undesirable effects of traditional pharmacology used for the inhibition of the central nervous system such as benzodiazepines (BZD). Phenolics, especially flavonoids and phlorotannins, have been considered as modulators of the BZD-site of GABA_A receptors (GABA_ARs), with sedative, anxiolytic or anticonvulsant effects. However, the wide chemical structural variability of flavonoids shows their potential action at more than one additional binding site on GABA_ARs, which may act either negatively, positively, by neutralizing GABA_ARs, or directly as allosteric agonists. Therefore, the aim of the present review is to compile and discuss an update of the role of phenolics, namely as pharmacological targets involving dysfunctions of the GABA system, analyzing both their different compounds and their mechanism as GABAergic modulators. We focus this review on articles written in English since the year 2010 until the present. Of course, although more research would be necessary to fully establish the type specificity of phenolics and their pharmacological activity, the evidence supports their potential as GABA_AR modulators, thereby favoring their inclusion in the development of new therapeutic targets based on natural products. Specifically, the data compiled in this review allows for the directing of future research towards ortho-dihydroxy diterpene galdosol, the flavonoids isoliquiritigenin (chalcone), rhusflavone and agathisflavone (biflavonoids), as well as the phlorotannins, dieckol and triphlorethol A. Clinically, flavonoids are the most interesting phenolics due to their potential as anticonvulsant and anxiolytic drugs, and phlorotannins are also of interest as sedative agents.