Identification and characterization of GABA(A) receptor modulatory diterpenes from Biota orientalis that decrease locomotor activity in mice

J Nat Prod. 2011 Aug 26;74(8):1764-72. doi: 10.1021/np200317p. Epub 2011 Jul 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Diterpenes / chemistry
  • Diterpenes / isolation & purification*
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • GABA Modulators / pharmacology
  • Male
  • Mice
  • Motor Activity / drug effects
  • Oocytes / drug effects
  • Receptors, GABA-A / drug effects*
  • Thuja / chemistry*
  • Xenopus laevis
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Anti-Anxiety Agents
  • Diterpenes
  • GABA Modulators
  • Receptors, GABA-A
  • gamma-Aminobutyric Acid
  • sandaracopimaric acid