Chemistry Reference
In-Depth Information
OH
H
2
N
O
glycine
O
O
N
Me
O
O
O
OH
N
O
O
strychnine
picrotoxinin
The best known Gly receptor ligand is strychnine, which is a potent competitive
antagonist and has been a highly valuable tool in the studies of Gly receptors.
Another antagonist is the convulsant picrotoxin, which is a noncompetitive antago-
nist of both GABA
A
and Gly receptors and is believed to bind to the channel-
forming region of the receptors. Electrophysiological studies showed that GB
antagonizes Gly receptors in neocortical slices
105
and hippocampal cells,
103
and
that the inhibition is noncompetitive, use-dependent, and probably voltage-
dependent, which thus indicates that GB binds to the central pore of the ion chan-
nel. It was also shown that GC and GM were almost equipotent to GB, whereas GA
and GJ were significantly less potent,
104,105
which suggests an important function of
the 1-OH group present in GB, GC, and GM, but absent in GA and GJ. This
assumption was corroborated by molecular modeling studies showing a striking
structural similarity between picrotoxinin, the active component of picrotoxin,
and ginkgolides;
105
the x-ray crystallographic structures of picrotoxinin and GB
were overlaid showing a remarkable similarity in the three-dimensional structure,
as indicated below. Thus, ginkgolides are highly useful pharmacological tools for
studying the function and properties of Gly receptors.
O
O
O
O
HO
O
O
O
O
HO
O
Me
O
O
O
O
O
Me
OH
O
Me
HO
HO
O
O
picrotoxinin
ginkgolide B
Although these studies showed that ginkgolides are selective antagonists of Gly
receptors, a recent study looking at recombinant a
1
b
2
g
2L
GABA
A
receptors showed
that ginkgolides are in fact moderately potent antagonists of these receptors, with K
i
values around 15 mM.
112
Another study suggested that GB might exhibit subunit
selectivity at Gly receptors, as GB preferentially blocks chloride channels formed
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