title: 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.
authors.affiliation: Division of Pharmaceutical Biology, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Zaugg
authors.forename: Sophia
authors.initials: S
authors.lastname: Khom
authors.forename: Daniela
authors.initials: D
authors.lastname: Eigenmann
authors.forename: Igor
authors.initials: I
authors.lastname: Baburin
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects*; D029783:Thuja / Q000737:chemistry*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D004224:Diterpenes; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C082072:sandaracopimaric acid