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analogs were much less potent than GB.
94
GB derivatives, many of which were
identical to those synthesized by Park et al. were prepared by Hu et al. with a
slightly modified procedure and obtained benzylated GB derivatives that were
more potent than GB.
95,96
Later, Hu et al. prepared various degradation and elim-
ination products of GA and GB, as well as amide derivatives lacking rings C and D,
but in all cases, decreased PAF receptor antagonism was observed.
97,98
One goal of SAR studies is to put forward a pharmacophore model that can elu-
cidate the activities of synthesized derivatives, as well as predict the activity of
novel derivatives. A three-dimensional quantitative SAR study
99
was attempted
for ginkgolides and the PAF receptor, using comparative molecular field analysis
and 25 ginkgolide analogs, mainly those synthesized by Corey et al.
54,55,90
In agree-
ment with the SAR studies just described, this pharmacophore model predicted that
substituents in the 10-OH position of GB would improve activity.
Clarification of the interactions between ginkgolides and the PAF receptor on a
molecular level can be carried out with photolabeling techniques; therefore, photo-
activatable derivatives of GB and GC were recently prepared.
100
This study gener-
ated highly potent analogs, with benzophenone, trifluoromethyldiazirine, and
tetrafluorophenyl azide groups in the 10-OH position of GB as the most active
with K
i
values of 90-150 nM. These derivatives are promising tools for character-
izing the PAF receptor-ginkgolide interaction. This study also provided the first
evaluation of the interaction of ginkgolides with the cloned PAF receptor using a
radioligand binding assay. In another recent study, the effect of acetate derivatives
of ginkgolides was investigated, which showed that acetylation generally decreases
antagonistic effects at the PAF receptor.
70
Recently, a study looked at the effect of
substitutions at the 7-position of ginkgolides and showed that in contrast to previous
reports, potent ginkgolide derivatives could be prepared by introducing chlorine;
7-chloro-GB, with a K
i
ΒΌ
110 nM, was eight-fold more potent than GB.
101
F
N
N
N
3
F
F
3
C
F
F
O
R =
R
O
O
O
HO
OO
t
Bu
O
Me
HO
O
O
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