Identification and Characterization of GABA_A Receptor Modulatory Diterpenes from Biota orientalis That Decrease Locomotor Activity in Mice

Abstract

An ethyl acetate extract of Biota orientalis leaves potentiated GABA-induced control current by 92.6% ± 22.5% when tested at 100 μg/mL in Xenopus laevis oocytes expressing GABA(A) receptors (α₁β₂γ(2S) subtype) in two-microelectrode voltage clamp measurements. HPLC-based activity profiling was used to identify isopimaric acid (4) and sandaracopimaric acid (5) as the compounds largely responsible for the activity. Sandaracopimaradienolal (3) was characterized as a new natural product. Compounds 4 and 5 were investigated for GABA(A) receptor subtype selectivity at the subtypes α₁β₁γ(2S), α₁β₂γ(2S), α₁β₃γ(2S), α₂β₂γ(2S), α₃β₂γ(2S), and α₅β₂γ(2S). Sandaracopimaric acid (5) was significantly more potent than isopimaric acid (4) at the GABA(A) receptor subtypes α₁β₁γ(2S), α₂β₂γ(2S), and α₅β₂γ(2S) (EC₅₀4: 289.5 ± 82.0, 364.8 ± 85.0, and 317.0 ± 83.7 μM vs EC₅₀5: 48.1 ± 13.4, 31.2 ± 4.8, and 40.7 ± 14.7 μM). The highest efficiency was reached by 4 and 5 on α₂- and α₃-containing receptor subtypes. In the open field test, ip administration of 5 induced a dose-dependent decrease of locomotor activity in a range of 3 to 30 mg/kg body weight in mice. No significant anxiolytic-like activity was observed in doses between 1 and 30 mg/kg body weight in mice.

GABAA receptor modulation by piperine and a non-TRPV1 activating derivative

“…Natural products from distinct structural classes including flavonoids [22–25], terpenoids [26–28], sesquiterpenes [29–31], diterpenes [32], triterpene glycosides [33], polyacetylenes [34], (neo)lignans [28,35], alkaloids [3] or (furano)coumarins [36,37] have been shown to modulate GABA A receptors.…”

GABAA Receptor Binding Assays of Standardized Leonurus cardiaca and Leonurus japonicus Extracts as Well as Their Isolated Constituents

“…Further data on the action of labdane-type diterpenes on the GABA system were recently published for the TCM plants Curcuma kwangsiensis S. G.Lee & C. F. Liang (Zingiberaceae) [19] and Biota orientalis (L.) Endl. (Cupressaceae) [20] as well as the South African Leonotis leonurus (L.) R. Br. (Lamiacea) [21].…”

Pharmacodynamics of potassium channel openers in cultured neuronal networks

“…In this study, we observed a significant potency shift of NS1619 under pentylenetetrazol, in a manner similar to flupirtine. Isopimaric acid also exhibited a GABAergic effect, although observed at a much lower EC 50 than that reported in the literature (around 300 mM; Zaugg et al, 2011). Unlike NS1619, isopimaric acid did not reduce the action potential duration, which is a consequence of BK channel activation (Scholz et al, 1998), and completely abolished network burst rate at concentrations lower than the EC 50 of spike production.…”