title: Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant alpha1beta2gamma2L GABA(A) receptors.
abstract: The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning. Bilobalide was found to antagonise the direct action of gamma-aminobutyric acid (GABA) on recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptors. The effect of bilobalide on the direct action of GABA at alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp method was evaluated and compared with the effects of the classical GABA(A) receptor competitive antagonist bicuculline and noncompetitive antagonist picrotoxinin. Bilobalide (IC(50)=4.6+/-0.5 microM) was almost as potent as bicuculline and pictrotoxinin (IC(50)=2.0+/-0.1 and 2.4+/-0.5 microM, respectively) at alpha(1)beta(2)gamma(2L) GABA(A) receptors against 40 microM GABA (GABA EC(50)). While bilobalide and picrotoxinin were clearly noncompetitive antagonists, the potency of bilobalide decreased at high GABA concentrations suggesting a component of competitive antagonism.
authors.affiliation: Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, NSW 2006, Sydney, Australia.
authors.forename: Shelley H
authors.initials: SH
authors.lastname: Huang
authors.forename: Rujee K
authors.initials: RK
authors.lastname: Duke
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Keiko
authors.initials: K
authors.lastname: Sasaki
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D020441:Ginkgo biloba / Q000737:chemistry*; D046934:Ginkgolides; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010852:Picrotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D054830:Sesterterpenes; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D001640:Bicuculline; D003517:Cyclopentanes; D004224:Diterpenes; D005663:Furans; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D046934:Ginkgolides; D010852:Picrotoxin; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D054830:Sesterterpenes; D005680:gamma-Aminobutyric Acid; C022961:picrotoxinin; C073710:bilobalide