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  • Methoxyflavone and methoxyflavanone Fig both act as flumazen

    2021-11-24

    6-Methoxyflavone and 6-methoxyflavanone (Fig. 2) both act as flumazenil-insensitive positive allosteric modulators of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABAA receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABAA receptors. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S, and ρ1W328M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine-sensitive ρ1I307S/W328M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonized by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABAA receptors and its partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids. Further studies on 6-substitued flavones are needed to study the LY 235959 receptor and the complex nature of the activation and modulation of GABAA receptor subtypes.
    Flavan-3-ol Esters The flavan-3-ol ester Fa131 (trans-(2S,3R)-3-acetoxy-4′-methoxyflavan, Fig. 3) is a selective positive modulator of α2-containing GABAA recombinant receptors and an anxiolytic in mice without sedation (Fernandez, Mewett, Hanrahan, Chebib, & Johnston, 2008). The diastereoisomeric flavan-3-ol ester with an additional 3′-methoxy, Fa173 (cis-(2S,3S)-3-acetoxy-3′,4′-dimethoxyflavan, Fig. 3) blocks the modulatory actions of Fa131 (Fernandez et al., 2012). Fa173 also blocks the positive modulatory action of the anesthetic etomidate, the sedative anticonvulsant loreclezole, and selectively blocks the low-affinity effect of diazepam (100μM) at α1β2γ2L GABAA receptors, but not the high-affinity effect of diazepam (100nM). Fa173 did not inhibit the positive modulation of GABA by the anesthetic propofol, barbiturate thiopental, or neuroactive steroid allopregnanolone. This suggested that Fa131, etomidate, loreclezole, and high doses of benzodiazepine all exert their positive modulatory effects via a common or overlapping binding site that can be blocked by the neutralizing modulator Fa173. Of these agents, Fa131 alone shows selectivity for α2-containing GABAA recombinant receptors. Fa131 and Fa173 were synthesized as simple analogues of the flavon-3-ol ester epigallocatechin gallate (EGCG, Fig. 3) found in green tea. EGCG acts as a negative modulator of GABAA receptors in high concentrations. At low concentrations, it has no direct effect on the action of GABA on GABAA receptors but potentiates the positive modulation by diazepam. This effect of modulating a modulator has been termed second-order modulation (Campbell, Chebib, & Johnston, 2004). Further evidence of the effects of EGCG on the modulation of GABAA receptors at the high-affinity benzodiazepine site come from studies on hippocampal neurones where the action of the negative modulator methyl β-carboline-3-carboxylate could be counteracted by EGCG (Vignes, 2013). The anxiolytic action of EGCG may involve a complex action on GABAA receptors.
    The natural flavan-3-ol (+)-catechin (Fig. 3) is an allosteric agonist at recombinant α4β3δ receptors expressed in oocytes (Eghorn et al., 2014). (+)-Catechin appears to be a positive allosteric modulator for the high-affinity binding of γ-hydroxybutyric acid (GHB) on these receptors. This action is stereoselective in that (−)-catechin is much less active. Interestingly, the related (+)-taxifolin (Fig. 3), which is identical to (+)-catechin except that it has a ketone in the 4 position, was a negative modulator. (+)-Catechin has been reported to have no action on recombinant α1β2γ2L GABAA receptors (Campbell et al., 2004), although relatively weak in activity (+)-catechin may aid in further characterization of the GHB high-affinity sites that are likely to be present on certain GABAA receptors.
    Natural Flavonoids and Related Compounds