Positive GABA(A) receptor modulators from Acorus calamus and structural analysis of (+)-dioxosarcoguaiacol by 1D and 2D NMR and molecular modeling

• Published in: Journal of natural products (Washington, D.C.) Vol. 74; no. 6; pp. 1437 - 1443
• Main Authors: Zaugg, Janine, Eickmeier, Eva, Ebrahimi, Samad Nejad, Baburin, Igor, Hering, Steffen, Hamburger, Matthias
• Format: Journal Article
• Language: English
• Published: United States 24-06-2011
• Subjects: Acorus - chemistry; Animals; GABA Modulators - pharmacology; Mice; Molecular Structure; Oocytes - drug effects; Receptors, GABA-A - metabolism; Rhizome - chemistry; Sesquiterpenes - chemistry; Sesquiterpenes - isolation & purification; Sesquiterpenes - pharmacology; Xenopus laevis
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np200181d

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.