Ginkgolides are antagonists of the inhi
bitory ligand-gated ion channels for the neurotransmitters glycineand
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-amino
butyric acid (GABA). In this study the ginkgolide structure was modified in order to investigatethe minimum structural requirements for glycine receptor antagonism. The five native ginkgolides and aseries of 29 ginkgolide derivatives were characterized at the three glycine receptor su
btypes
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1,
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1
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beta2.gif" BORDER=0 ALIGN="middle">, and
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2, which revealed that only minor changes in the ginkgolide skeleton were allowed for maintaining glycinereceptor antagonism. A pharmacophore model was generated and applied in a virtual screening of a compounddata
base (300 000 compounds), resulting in the identification of 31 hits. Twenty-seven of these hits werescreened for
biological activity,
but none displayed antagonist activity at the glycine receptors. This stronglysuggests the importance of other pharmacophore components in the
binding of ginkgolides to glycine receptors,and we propose that the structural rigidity of the ginkgolide molecule may
be crucial for its glycine receptoractivity.