Ferulic Acid Esters and Withanolides: In Search of Withania somnifera GABA_A Receptor Modulators

Nine compounds, including two undescribed withanolides, withasomniferolides A and B (1 and 2), three known withanolides (3-5), a ferulic acid dimeric ester (6), and an inseparable mixture of three long alkyl chain ferulic acid esters (7-9), were isolated from a GABA_A receptor positive activator methanol extract of the roots of Withania somnifera. The structures of the isolated compounds were elucidated based on NMR, MS, and ECD data analysis. In order to bioassay the single ferulic acid derivatives, compounds 6-9 were also synthesized. The most active compound, docosanyl ferulate (9), was able to enhance the GABA_A receptor inhibitory postsynaptic currents with an IC₅₀ value of 7.9 μM. These results, by showing an ability to modulate the GABA_A receptor function, cast fresh light on the biological activities of the secondary metabolites of W. somnifera roots.