Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors

g-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian central nervous system (CNS), with 25–50 % of synapses being GABA-ergic in nature. GABA influences neurons via three major classes of receptors, which are grouped on the basis of their subunit composition, gating properties, and pharmacological profiles, and termed GABAA, GABAB, and GABAC (GABA 1) receptors. GABAA and GABAC receptors are ligand-gated chloride ion channels, whereas GABAB receptors are G protein-coupled receptors. [2] The ionotropic GABAA receptors are transmembrane protein complexes composed of five heteropentameric subunits. To date, 16 human GABAA receptor subunits have been identified, and they have been classified into a (a1–a6), b (b1–b3), g (g1– g3), d, e, p, and q. Although a wide range of different GABAA receptor combinations exists in vivo, the a1b2g2 subunit combination represents the most dominant receptor subtype in the human brain. 3] Enhancement of chloride ion flux at GABAA receptors by positive modulators is one of the most powerful therapeutic strategies for the treatment of CNS-related disorders, such as generalized anxiety, panic disorders, sleep disturbances, muscle spasms and seizure disorders. 4] Positive modulators of GABAA receptors, such as benzodiazepines, neuroactive steroids, barbiturates, and loreclezole, have been identified as useful for the treatment of CNS-related disorders. Benzodiazepines are commonly prescribed drugs, but they produce a range of both desirable and unwanted side effects, such as sedation, myorelaxation, rebound anxiety, dependence, tolerance, strong interactions with alcohol, and amnesia. 5] However, based on recent advances in GABAA receptor pharmacology, subtype-selective agents and modulators that bind to the GABAA receptor at sites other than the classical benzodiazepine binding site may offer an opportunity to discover novel therapeutic agents with fewer adverse side effects. 6] Thus, the identification of novel templates for positive modulation of GABAA receptors represent an important objective in drug discovery for the treatment of CNS-related disorders. Using functional electrophysiological studies on recombinant receptors, we and others recently revealed that flavonoids (flavones/flavanones/flavan-3-ols) are able to interact with binding sites on the GABAA receptor that are independent of the classical high-affinity, flumazenil-sensitive, benzodiazepine binding site. In contrast, many previous studies demonstrated that a range of naturally occurring and synthetic flavonoids displace radiolabelled benzodiazepines in rat brain tissue binding to the high-affinity benzodiazepine binding site with nanomolar affinity. Thus, the benzopyran-4-one (flavonoid) pharmacophore is emerging as a potential template for the treatment of CNS-related disorders, although the exact mechanism and location of the binding site have not yet been elucidated. Isoflavones are a subgroup of flavonoids, which differ from flavones in location of the substituted phenyl group (Figure 1). Isoflavones are natural antioxidants and have diverse effects