Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin

HPLC-based activity profiling for GABAA receptor modulators from the traditional Chinese herbal drug Kushen (Sophora flavescens root)

“…For further evaluation of compounds in the active time windows, 6, 7, and 9-16 (10 μM) were co-applied with a GABA (EC [3][4][5][6][7][8][9][10] ) to oocytes expressing α 1 β 2 γ 2S receptors. Kushenol I (7), (-)-kurarinone (9), sophoraflavanone G (13), and kuraridine (15) induced the strongest I GABA enhancement (Fig.…”

“…b Chloride currents through α 1 β 2 γ 2S GABA A receptors induced by GABA EC 3-10 (control; left column) and currents during co-application of GABA (EC [3][4][5][6][7][8][9][10] ) and 100 μg/mL of the Sophora flavescens extract (right column) a Potentiation of I GABA through α 1 β 2 γ 2S GABA A receptors by 10 μM of norkurarinol (0 ± 0%, n = 2), kushenol I (216.5 ± 29.3%, n = 5), (-)-kurarinone (362.3 ± 23.8%, n = 5), kushenol X (21.6 ± 3.4%, n = 2), neokurarinol (13.7±4.6%), n = 2), kushenol C (0±0%, n = 2, sophoraflavanone G (211.6±18.6%, n = 3), leachianone A (13.1±5.1%, n = 2), kuraridine (719.7±140.3%, n = 3), and kushenol A (53.1 ± 3.1%, n = 2). b Representative currents through α 1 β 2 γ 2S GABA A receptors induced by GABA (EC 3-10 , single bar, control) and traces recorded during co-application of GABA (EC [3][4][5][6][7][8][9][10] ) and the indicated compound (double bar). Current potentiation induced by the four most active compounds, kushenol I Summary of preliminary structure activity information on lavandulyl flavonoids and calculated physicochemical data for (-)-kurarinone (9) (from Pubchem) …”

“…Oocytes with maximal current amplitudes >3 μA were discarded to exclude voltage clamp errors. Before application of test solutions, a dose-response experiment with GABA concentrations ranging from 0.1 to 1 mM was performed to determine GABA EC [3][4][5][6][7][8][9][10] (typically between 3 and 10 μM).…”

“…After addition of GABA EC [3][4][5][6][7][8][9][10] , 100 μL of this solution was applied to the oocytes at a perfusion speed of 300 μL/s. Stock solutions of compounds 6-16 (10 mM in DMSO) were diluted to a concentration of 100 μM with bath solution and then mixed with GABA EC [3][4][5][6][7][8][9][10] . Of each solution, 100 μL was applied to the oocytes at a speed of 300 μL/s.…”

“…Various natural products modulating GABA A receptors (e.g., flavonoids, monoterpenes, diterpenes, neolignans, β-carbolines, and polyacetylenes) have been identified [9,10]. Given the diversity of these natural product ligands which structurally differ from synthetic GABA A receptor modulators, we recently initiated a project aiming at the discovery of GABA A receptor agonists with natural product scaffolds new for the target.…”