Phytochemical profiling of Curcuma kwangsiensis rhizome extract, and identification of labdane diterpenoids as positive GABAA receptor modulators

Abstract

An ethyl acetate extract of Curcuma kwangsiensis S.G. Lee & C.F. Liang (Zingiberaceae) rhizomes (100 μg/ml) enhanced the GABA-induced chloride current (IGABA) through GABAA receptors of the α1β2γ2S subtype by 79.0±7.0%. Potentiation of IGABA was measured using the two-microelectrode voltage-clamp technique and Xenopus laevis oocytes. HPLC-based activity profiling of the crude extract led to the identification of 11 structurally related labdane diterpenoids, including four new compounds. Structure elucidation was achieved by comprehensive analysis of on-line (LC-PDA-ESI-TOF-MS) and off-line (microprobe 1D and 2D NMR) spectroscopic data. The absolute configuration of the compounds was established by comparison of experimental and calculated ECD spectra. Labdane diterpenes represent a new class of plant secondary metabolites eliciting positive GABAA receptor modulation. The highest efficiency was observed for zerumin A (maximum potentiation of IGABA by 309.4±35.6%, and EC50 of 24.9±8.8 μM).

Keywords: CE; CPCM; Cotton effect; Curcuma kwangsiensis; ECD; Electronic circular dichroism (ECD); GABA; GABA(A) receptor modulation; GABA-induced chloride current; HPLC-based activity profiling; I(GABA); Labdane diterpenoids; OPLS; SCRF; TCM; TDDFT; Xenopus oocyte assay; Zingiberaceae; conductor-like polarizable continuum model; electronic circular dichroism; gamma-aminobutyric acid; optimized potential for liquid simulations; self-consistent reaction field; time-dependent density function theory; traditional Chinese medicine.