title: Positive GABA(A) receptor modulators from Acorus calamus and structural analysis of (+)-dioxosarcoguaiacol by 1D and 2D NMR and molecular modeling.
abstract: In a two-microelectrode voltage clamp with Xenopus laevis oocytes, a petroleum ether extract of Acorus calamus rhizomes enhanced the GABA-induced chloride current through GABA(A) receptors of the α₁β₂γ(2S) subtype by 277% ± 9.7% (100 μg/mL). β-Asarone (1), (+)-dioxosarcoguaiacol (2), (+)-shyobunone (3), and (+)-preisocalamenediol (4) were subsequently identified as main active principles through HPLC-based activity profiling and targeted isolation. The compounds induced maximum potentiation of the chloride current ranging from 588% ± 126% (EC₅₀: 65.3 ± 21.6 μM) (2) to 1200% ± 163% (EC(50): 171.5 ± 34.6 μM) (1), whereas (-)-isoshyobunone (5) and (-)-acorenone (6) exhibited weak GABA(A) modulating properties (5: 164% ± 42.9%; EC₅₀: 109.4 ± 46.6 μM and 6: 241% ± 23.1%; EC₅₀: 34.0 ± 6.7 μM). The relative configuration of 2 was established as 4R*8S*10R* by NOESY experiments and conformational analysis.
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: Eva
authors.initials: E
authors.lastname: Eickmeier
authors.forename: Samad Nejad
authors.initials: SN
authors.lastname: Ebrahimi
authors.forename: Igor
authors.initials: I
authors.lastname: Baburin
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
mesh_terms: D029023:Acorus / Q000737:chemistry*; D000818:Animals; D018757:GABA Modulators / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism*; D027343:Rhizome / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D018757:GABA Modulators; D011963:Receptors, GABA-A; D012717:Sesquiterpenes; C561438:dioxosarcoguaiacol