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J. Biol. Chem., Vol. 278, Issue 49, 49279-49285, December 5, 2003

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Terpene Trilactones from Ginkgo biloba Are Antagonists of Cortical Glycine and GABA_A Receptors^*

Lidija Ivic, Tristan T. J. Sands, Nathan Fishkin¶, Koji Nakanishi¶, Arnold R. Kriegstein||, and Kristian Strømgaard¶**

From the Department of Neurology, College of Physicians & Surgeons and the Integrated Program in Cellular, Molecular and Biophysical Studies, Columbia University, New York, New York 10032 and the ^¶Department of Chemistry, Columbia University, New York, New York 10027

Glycine and -aminobutyric acid, type A (GABA_A) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA_A receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA_A receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA_A and recombinant glycine -homomeric receptor antagonist.

Received for publication, April 17, 2003 , and in revised form, September 18, 2003.

^* This research was supported by National Institutes of Health Grant NS 38658 and the Alfred Benzon Foundation (to K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Present address: Dept. of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

^|| To whom correspondence should be addressed. Tel.: 212-305-4275; Fax: 212-305-3986; E-mail: ark17{at}columbia.edu.

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