MEDICINAL CHEMISTRY OF GINKGOLIDES FROM GINKGO BILOBA - Medicinal Chemistry of Bioactive Natural Products - page 314

by heteromeric Gly receptors in hippocampal pyramidal neurons of rat. 113 The
study, however, only showed a small difference, and studies on cloned Gly recep-
tors are required to clarify this point.
Because the interaction of ginkgolides and Gly receptors was only discovered
recently, the number of SAR studies carried out is also limited. In addition to
that mentioned here, one study has looked at the five native ginkgolides, as well
as at one synthetic ginkgolide (HE-196), showing that GB and GC are the most
potent with IC 50 values of 0.273 and 0.267 mM, respectively, whereas GA and
GJ had IC 50 values around 2 mM. 114 In the same study, the effects on glutamate-
gated ion channels, such as N-methyl- D -aspartate and a-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid receptors, was examined, and ginkgolides had
essentially no effect on these receptors. 114
To date, only one SAR study has been carried out in which 40 novel ginkgolide
derivatives were tested for their ability to antagonize the Gly receptor. 115 GC served
as the template, because GC is one of the most potent ginkgolides, and GC has the
most hydroxyl groups, which thus allows more diverse functionalizations of these
groups. All derivatives were substituted on one or more of the hydroxyl groups in
GC, including rearranged iso-ginkgolides and substituents of varying size. The deri-
vatives were investigated in a fluorescence-based membrane potential assay, 116 and
somewhat surprisingly, all novel derivatives were significantly less potent than
GC. 115 Thus, this result suggests important functions for the hydroxyl groups in
ginkgolides.
The studies carried out so far clearly demonstrate that the effect on Gly receptors
is distinct from the effect on PAF receptors, as SAR studies have shown that the
structural requirements are different for the two receptors. The potential importance
of the antagonism of Gly receptors also remains to be investigated.

7.4 VARIOUS EFFECTS OF GINKGOLIDES

The interactions of ginkgolides with the PAF and Gly receptors described above are
the best-characterized interactions of ginkgolides with targets found in the CNS.
Varying effects of ginkgolides have been observed using numerous assays with dif-
ferent tissues and conditions. No study has provided a clear-cut target for ginkgo-
lides but instead has introduced many different pharmacological effects that may or
may not be related to the targets described.
Ginkgolides have, however, modulating effects on several targets. One of the
best characterized is the modulation of peripheral benzodiazepine (PB) receptors.
The PB receptors are located mainly in peripheral tissues and glial cells in the brain
and are distinct from the benzodiazepine site on GABA A receptors. 117,118 The func-
tion of PB receptors is not entirely clear, but they have been suggested to be
involved in steroidogenesis, cell proliferation, and stress and anxiety disorders.
The latter is supported by an increase in the number of PB receptors in specific
brain regions in neurodegenerative disorders and after brain damage. 117 Initially
it was shown that the ligand binding capacity of PB receptors was decreased along