| Abstract
| - Ginkgolides are antagonists of the inhibitory ligand-gated ion channels for the neurotransmitters glycineand γ-aminobutyric 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 subtypes α1, α1β, andα2, 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 compounddatabase (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.
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