Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Eur J Pharmacol
2011 Oct 01;6681-2:57-64. doi: 10.1016/j.ejphar.2011.06.034.
Show Gene links
Show Anatomy links
Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.
Singhuber J
,
Baburin I
,
Ecker GF
,
Kopp B
,
Hering S
.
???displayArticle.abstract???
The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators.
P 19614-B11 Austrian Science Fund FWF, W 1232-B11 Austrian Science Fund FWF, P 19614 Austrian Science Fund FWF, W 1232 Austrian Science Fund FWF, FWF_P 19614 Austrian Science Fund FWF, FWF_W 1232 Austrian Science Fund FWF
Baburin,
Automated fast perfusion of Xenopus oocytes for drug screening.
2006, Pubmed,
Xenbase
Baburin,
Automated fast perfusion of Xenopus oocytes for drug screening.
2006,
Pubmed
,
Xenbase
Baburin,
Estimating the efficiency of benzodiazepines on GABA(A) receptors comprising gamma1 or gamma2 subunits.
2008,
Pubmed
,
Xenbase
Baur,
Novel plant substances acting as beta subunit isoform-selective positive allosteric modulators of GABAA receptors.
2005,
Pubmed
,
Xenbase
Bergendorff,
Furanocoumarins with affinity to brain benzodiazepine receptors in vitro.
1997,
Pubmed
Boileau,
Effects of gamma2S subunit incorporation on GABAA receptor macroscopic kinetics.
2003,
Pubmed
,
Xenbase
Dekermendjian,
Characterisation of the furanocoumarin phellopterin as a rat brain benzodiazepine receptor partial agonist in vitro.
1996,
Pubmed
Demel,
Ensemble Rule-Based Classification of Substrates of the Human ABC-Transporter ABCB1 Using Simple Physicochemical Descriptors.
2010,
Pubmed
Epifano,
Neuroprotective effect of prenyloxycoumarins from edible vegetables.
2008,
Pubmed
Fernandez,
Flavan-3-ol derivatives are positive modulators of GABA(A) receptors with higher efficacy for the alpha(2) subtype and anxiolytic action in mice.
2008,
Pubmed
,
Xenbase
Gebauer,
Synthesis and structure-activity relationships of novel warfarin derivatives.
2007,
Pubmed
Granger,
(+)- And (-)-borneol: efficacious positive modulators of GABA action at human recombinant alpha1beta2gamma2L GABA(A) receptors.
2005,
Pubmed
,
Xenbase
Hirsh,
Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.
2001,
Pubmed
Huen,
Naturally occurring 2'-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands.
2003,
Pubmed
,
Xenbase
Johnston,
Modulation of ionotropic GABA receptors by natural products of plant origin.
2006,
Pubmed
Khom,
Pharmacological properties of GABAA receptors containing gamma1 subunits.
2006,
Pubmed
,
Xenbase
Khom,
Valerenic acid potentiates and inhibits GABA(A) receptors: molecular mechanism and subunit specificity.
2007,
Pubmed
,
Xenbase
Korpi,
Drug interactions at GABA(A) receptors.
2002,
Pubmed
Kostova,
Synthetic and natural coumarins as cytotoxic agents.
2005,
Pubmed
Kostova,
Synthetic and natural coumarins as antioxidants.
2006,
Pubmed
Li,
HPLC-based activity profiling for GABA(A) receptor modulators: a new dihydroisocoumarin from Haloxylon scoparium.
2010,
Pubmed
,
Xenbase
Luszczki,
Time-course and dose-response relationships of imperatorin in the mouse maximal electroshock seizure threshold model.
2007,
Pubmed
Luszczki,
Imperatorin enhances the protective activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice.
2007,
Pubmed
Luszczki,
Osthole suppresses seizures in the mouse maximal electroshock seizure model.
2009,
Pubmed
Luszczki,
Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: a comparative study.
2009,
Pubmed
McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed
Mody,
Diversity of inhibitory neurotransmission through GABA(A) receptors.
2004,
Pubmed
Olsen,
GABA A receptors: subtypes provide diversity of function and pharmacology.
2009,
Pubmed
Piao,
Antioxidative activity of furanocoumarins isolated from Angelicae dahuricae.
2004,
Pubmed
Priestley,
Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABA(A) receptors and a homo-oligomeric GABA receptor from Drosophila melanogaster.
2003,
Pubmed
,
Xenbase
Sadler,
Medicine: K is for koagulation.
2004,
Pubmed
Senate Commission on Food Safety, German Research Foundation,
Toxicological assessment of furocoumarins in foodstuffs.
2007,
Pubmed
Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed
Sieghart,
Structure, pharmacology, and function of GABAA receptor subtypes.
2006,
Pubmed
Sieghart,
Subunit composition, distribution and function of GABA(A) receptor subtypes.
2002,
Pubmed
Simon,
Analysis of the set of GABA(A) receptor genes in the human genome.
2004,
Pubmed
Thanh,
Cytotoxic coumarins from the root of Angelica dahurica.
2004,
Pubmed
Trauner,
Modulation of GABAA receptors by valerian extracts is related to the content of valerenic acid.
2008,
Pubmed
,
Xenbase
Tsassi,
Antimicrobial coumarins from the stem bark of Afraegle paniculata.
2010,
Pubmed
Vogl,
Identification and quantification of coumarins in Peucedanum ostruthium (L.) Koch by HPLC-DAD and HPLC-DAD-MS.
2011,
Pubmed
Widelski,
Coumarins from Angelica lucida L.--antibacterial activities.
2009,
Pubmed
Yang,
Cytotoxic activity of coumarins from the fruits of Cnidium monnieri on leukemia cell lines.
2003,
Pubmed
Zaugg,
HPLC-based activity profiling: discovery of piperine as a positive GABA(A) receptor modulator targeting a benzodiazepine-independent binding site.
2010,
Pubmed
,
Xenbase
Zaugg,
HPLC-based activity profiling of Angelica pubescens roots for new positive GABAA receptor modulators in Xenopus oocytes.
2011,
Pubmed
,
Xenbase
