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 α 1 β 2 γ 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% (EC 50 : 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%; EC 50 : 109.4 ± 46.6 μM and 6: 241% ± 23.1%; EC 50 : 34.0 ± 6.7 μM). The relative configuration of 2 was established as 4R*8S*10R* by NOESY experiments and conformational analysis.Acorus calamus L. (Acoraceae), commonly known as "sweet flag", is a polyploidic marsh plant indigenous to Asia and is now distributed along trade routes all over the northern hemisphere. 1 The aromatic rhizome has been widely used as an herbal remedy. It contains 1.7-9.3% of a volatile oil composed of monoterpenes, sesquiterpenes, and phenylpropanoids. The most characteristic constituent of the oil is β-asarone, even though Europe PMC Funders GroupAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2011 October 24. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts its concentration may vary considerably (96% in the tetraploidic form found in eastern and tropical southern Asia, 5% in the triploidic form found in Europe, Himalayan, and temperate Indian regions, and 0% in the diploidic variety growing from North America to Siberia). [1][2][3][4] In European folk medicine, A. calamus rhizomes have been mainly used as "Amarum aromaticum" to alleviate gastrointestinal ailments such as acute and chronic dyspepsia, gastritis and gastric ulcer, intestinal colic, and anorexia. 5,6 Ayurvedic medicine and traditional Chinese medicine (TCM) use the drug preferably to treat central nervous system (CNS) related diseases such as epilepsy, insanity, mental weakness, or insomnia. 7-9 Several in vivo studies support a sedative and tranquillizing action of the essential oil and of ethanolic and aqueous extracts of A. calamus. [10][11][12] Up to now, the underlying mechanism of action has remained elusive despite various investigations, even though the pharmacological effect could be mainly attributed to α-asarone and β-asarone. 11,[13][14][15] GABA A receptors are pentameric ligand-gated chloride ion channels that are activated by GABA, the major inhibitory neurotransmitter in the CNS. Most likely more than 11 different receptor subtypes, assembled from five varying subunits, exist in the human brain. These are involved in distinct neuronal circuits and are targeted by numerous classes of drugs such as benzodiazepines, barbiturates, and some general anesthetics. The most abundant GABA...

Alpha-asarone from Acorus gramineus alleviates epilepsy by modulating A-Type GABA receptors

“…Based on the latest finding that b-asarone potentiated the response of recombinant GABA A Rs expressed in Xenopus oocytes (Zaugg et al, 2011), we hypothesized that a-asarone might exert its effect through activation of GABA A Rs. As shown in Fig.…”

Peroxy natural products

“…This compound has now been isolated from Acorus calamus. 172 Chemical examinations of the roots of Nardostachys chinensis afforded two antimalarial guaiane endoperoxides, nardoperoxide 305 and isonardoperoxide 306, whose absolute stereochemistries were determined by CD spectra. The endoperoxide moiety of the molecules was assumed to relate to the antimalarial activity.…”

Formulas Used by Tibetan Doctors at Men‐Tsee‐Khang in India for the Treatment of Neuropsychiatric Disorders and Their Correlation with Pharmacological Data

“…Synergism may also involve multitarget effects by acting on enzymes, metabolites, proteins, receptors, and ionic channels (Wagner and Ulrich-Merzenich, 2009). There are several examples of synergism in plants or formulations with psychoactive effects, including Cannabis sativa L., which is a therapeutic agent with analgesic, muscle relaxant, sedative, appetite enhancement, and (Hazra et al, 2007); anticonvulsant (Manis et al, 1991); sedative (Bhattacharya, 1968); CNS depressant (Zaugg et al, 2011); anticholinesterasic and memory enhancer (Mukherjee et al, 2007); neuroprotective (Palani et al, 2010); behavioral changes (Shukla et al, 2006). (Wang et al, 2010); antioxidant (Saleem et al, 2006); antiparkinson (Ahmad et al, 2005); anxiolytic (Hosseinzadeh & Noraei, 2009); hypnotic (Hosseinzadeh & Noraei, 2009); memory enhancer (Pitsikas et al, 2007) 22.…”

“…Differently from the previous two species, sweet flag (Acorus calamus L.) is specifically used to treat rLung disorders. Indeed, Zaugg et al (2011) tested several compounds derived from a petroleum ether extract of this plant, and all of them showed potentiation of the GABA-A receptor chloride current. Its protective effect has been demonstrated in different rat models, as acetaminophen induced nephrotoxicity (Palani et al, 2010) and middle cerebral artery occlusion (Shukla et al, 2006).…”