Ginkgolides are antagonists of the inhibitory ligand-gated ion channels for the neurotrans
mitters glycineand
![](/i<font color=)
mages/gifchars/ga
mma.gif" BORDER=0 >-a
minobutyric acid (GABA). In this study the ginkgolide structure was
modified in order to investigatethe
mini
mu
m structural require
ments for glycine receptor antagonis
m. The five native ginkgolides and aseries of 29 ginkgolide derivatives were characterized at the three glycine receptor subtypes
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>1,
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>1
![](/i<font color=)
mages/gifchars/beta2.gif" BORDER=0 ALIGN="
middle">, and
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>2, which revealed that only
minor changes in the ginkgolide skeleton were allowed for
maintaining glycinereceptor antagonis
m. A phar
macophore
model was generated and applied in a virtual screening of a co
mpounddatabase (300 000 co
mpounds), 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 i
mportance of other phar
macophore co
mponents 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.