Many natural flavonoids have been

Many natural flavonoids have been identified as influencing ionotropic GABA receptors through bioassay-guided fractionation of plant extracts (Fig. 4). HPLC-based activity profiling of extracts the traditional Chinese herbal drug Kushen (Sophora flavescens root) led to the identification of the 8-lavandulyl flavonoids, kushenol I, sophoraflavanone G, and (−)-kurarinone, and the related chalcone kuraridine as GABAA receptor modulators (Yang, Baburin, Plitzko, Hering, & Hamburger, 2011). The 8-lavandulyl flavonoids are first representatives of a novel scaffold for this target. Salvia continues to be a rich source of GABAA modulators (Kavvadias et al., 2003, Kavvadias et al., 2004). Salvia triloba, traditionally known as Greek sage on bioassay-guided fractionation yielded a variety of flavonoids and terpenoids as modulators (Abdelhalim, Chebib, Aburjai, Johnston, & Hanrahan, 2004) (Fig. 4). The flavonoids salvigenin, cirsimaritin, and hispidulin acted as positive modulators when applied in the presence of low concentrations of GABA, but in the presence of high concentrations of GABA acted as negative modulators, demonstrating a biphasic action. A range of natural flavonoids, including quercetin (Fig. 4), act as negative modulators of GABAC receptors containing ρ-subunits (Goutman, Waxemberg, Donate-Oliver, Pomata, & Calvo, 2003). The receptors are insensitive to the classic flumazenil-sensitive high-affinity modulation by benzodiazepines. Further studies have shown that quercetin antagonizes GABAC receptors through a redox-independent allosteric mechanism that is prevented by ascorbic hundreds of people (Calero et al., 2013). Glabrol (Fig 5), the major flavonoid in extracts of liquorice (Glycyrrhiza glabra, GG), is a flumazenil-sensitive positive modulator of GABAA receptors (Cho et al., 2012). Glabrol increased sleep duration and decreased sleep latency in a dose-dependent manner. The molecular structure and pharmacophore modeling of glabrol indicate that the isoprenyl groups of glabrol may play a key role in its activity. Glabridin (Fig 5), another sedative-hypnotic flavonoid in extracts of liquorice, is a flumazenil-insensitive positive modulator of GABAA receptors in dorsal raphe neurons (Jin et al., 2013). Glabrol is a flavanone, whereas glabridin is an isoflavan. A series of synthetic isoflavones have also been shown to act as modulators at recombinant GABAA receptors. 2-Ethyl-7-hydroxy-3′,4′-methylenedioxy-6-propyl-isoflavone (Fig. 5) was the most potent and efficacious of the positive modulators, while 3′,5′,7-trihydroxyisoflavone (Fig. 5) was the most active of the negative modulators (Gavande, Karim, Johnston, Hanrahan, & Chebib, 2011). The actions of both compounds were flumazenil-insensitive. The variation in activity of these isoflavonoids suggests that further studies of subtype selectivity are warranted.
Conclusion Understanding the structural determinants of flavonoid effects on ionotropic GABA receptors and developing agents specific for ionotropic GABA receptor subtypes remain a key challenge. Natural flavonoids are a significant part of our diet. As they may readily cross the blood–brain barrier, it is important that we understand how natural flavonoids might influence brain function. Synthetic flavonoids are attractive leads for drugs to treat brain dysfunction. They are useful for investigating the role of the modulatory sites at GABAA receptors, determining potential binding sites and the development of GABAA subtype selective agents. Significant progress has been made since our 2011 review (Hanrahan et al., 2011), but much remains to be done.
Conflict of Interest
Acknowledgments
Introduction γ-Aminobutyric acid (GABA) mediates its effects, in part, by the activation of GABAA receptors (GABAARs). GABAARs are members of the Cys-loop family of ligand-gated ion channels that mediate most of the inhibitory neurotransmission in the central nervous system (Chebib and Johnston, 2000, Olsen and Sieghart, 2008). These receptors are pentameric constructs, arranged around a central chloride-conducting pore (Chebib and Johnston, 2000, Olsen and Sieghart, 2008). Individual GABAAR subunits that form the pentamer are encoded by a number of genes, including α(1-6), β(1-4), γ(1-3), δ, π, and ε subunits (Chebib and Johnston, 2000, Olsen and Sieghart, 2008). These subunits are believed to assemble into a number of functional receptor subtypes that differ in their pharmacology, sensitivity to GABA, brain distribution and physiology (Olsen and Sieghart, 2008).