A dichloromethane extract of stems and roots of Pholidota chinensis (Orchidaceae) enhanced GABA-induced chloride currents (I(GABA)) by 132.75 ± 36.69% when tested at 100 μg/mL in a two-microelectrode voltage clamp assay, on Xenopus laevis oocytes expressing recombinant α₁β₂γ₂S GABA(A) receptors. By means of an HPLC-based activity profiling approach, the three structurally related stilbenoids coelonin (1), batatasin III (2), and pholidotol D (3) were identified in the active fractions of the extract. Dihydrostilbene 2 enhanced I(GABA) by 1512.19 ± 176.47% at 300 μM, with an EC₅₀ of 52.51 ± 16.96 μM, while compounds 1 and 3 showed much lower activity. The relevance of conformational flexibility for receptor modulation by stilbenoids was confirmed with a series of 13 commercially available stilbenes and their corresponding semisynthetic dihydro derivatives. Dihydrostilbenes showed higher activity in the oocyte assay than their corresponding stilbenes. The dihydro derivatives of tetramethoxy-piceatannol (12) and pterostilbene (20) were the most active among these derivatives, but they showed lower efficiencies than compound 2. Batatasin III (2) showed high efficiency but no significant subunit specificity when tested on the receptor subtypes α₁β₂γ₂s, α₂β₂γ₂s, α₃β₂γ₂s, α₄β₂γ₂s, α₅β₂γ₂s, α₁β₁γ₂s, and α₁β₃γ₂s. Dihydrostilbenes represent a new scaffold for GABA(A) receptor modulators.
Keywords: Dihydrostilbenes; GABA(A) receptor modulators; HPLC-based activity profiling; Pholidota chinensis.
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