MEDICINAL CHEMISTRY OF GINKGOLIDES FROM GINKGO BILOBA - Medicinal Chemistry of Bioactive Natural Products - page 312

In 2003, Krane et al. used a functional assay, microphysiometry, to evaluate the
effects of ginkgolides on the human PAF receptor. GB and 10-O-benzyl-GB showed
81% and 93% (100-mM concentration) inhibition, respectively, of the PAF receptor
response, the latter being equivalent to the effect of WEB2086. G. biloba extract
mixtures were also tested, which indicated potential synergistic effects among
the components in the extract. 102

Bulky/aromatic
substituents
increases activity

O Lactone C essential

for activity

HO

O

C

HO

tert -butyl group
increases activity

O

O

Lactone F can be
replaced by lipo-
philic groups

F

D

A

O B

THF-ring D
essential for activity

H 3 C E

7

HO

OH

O

O

7-OH decreases and
7-Cl increases activity

Thus, several ginkgolide derivatives that have been prepared and tested for their
ability to antagonize the PAF receptor have resulted in a good understanding of the
structural features required for inhibition. Clearly, a step forward in this understand-
ing this interaction would come from photolabeling experiments or similar studies
providing a more detailed insight. More investigation is required to determine the
potential physiological effects in the CNS.

7.3 GINKGOLIDES AND GLYCINE RECEPTORS

Until 2002, the only specific target for ginkgolides was the PAF receptor, whose
importance in CNS functions is not clear. Therefore, the recent finding that GB
was a potent and selective antagonist of Gly receptors 103-105 provided an important
target for additional studies on the neuromodulatory properties of ginkgolides.
The Gly receptors are found primarily in the spinal cord and brain stem but
also in higher brain regions such as the hippocampus. They are, together with g-
aminobutyric acid (GABA A ) receptors, the main inhibitory receptors in the
CNS. 106,107 Both Gly and GABA A receptors are ligand-gated ion channels that,
together with nicotinic acetylcholine (nACh) and serotonin (5-HT 3 ) receptors, con-
stitute a superfamily of membrane-bound receptors that mediate fast chemical
synaptic transmission in the CNS. 108 Gly receptors share several structural simila-
rities with these receptors, including a pentameric arrangement of subunits, each
composed of four transmembrane domains (M1-M4) and an extracellular N-
terminal 15-residue cysteine-loop motif. 109 Recently, there has been a renewed
interest in ligands for Gly receptors, because modulators of the Gly receptor func-
tion could serve as muscle relaxants as well as sedative and analgesic agents. 110 A
recent study suggests that a3 homomeric Gly receptors are important mediators of
pain. 111