Biomedical Engineering Reference
In-Depth Information
and CP-101,606 (
15.57
) represent an important series of noncompetitive NMDA receptor antagonists.
These compounds are active in ischemia models and as anticonvulsants and antinociceptive agents.
Early clinical trials with these analogs have been disappointing due to unwanted effects. The side
effect proi les do however seem to be signii cantly improved as compared to, e.g., competitive NMDA
antagonists.
15.7.4 T
HE
G
LYCINE
C
OAGONIST
S
ITE
The excitatory coagonist site for glycine (
15.58
) at the NMDA receptor is named the glycine
B
recep-
tor. This receptor site is different from the inhibitory glycine receptors found primarily in the spi-
nal cord of the mammalian CNS, where glycine activates strychnine-sensitive ionotropic receptors
named as glycine
A
receptors. Glycine
B
receptors seem to modulate the level of activity at NMDA
receptors. A certain concentration level of glycine is always present in the synapse. Thus, Glu acti-
vates the NMDA receptors, whereas the level of glycine can modulate this activity and possibly
control receptor desensitization. (
R
)-Serine (
15.59
) is a potential endogenous agonist at glycine
B
receptors.
Limited success of competitive NMDA receptor antagonists as therapeutic agents has focused
attention on the glycine
B
site. (
R
)-Cycloserine (
15.60
) and (
R
)-HA-966 (
15.61
) are partial glycine
agonists, capable of penetrating the BBB after systemic administration. (
R
)-Cycloserine (
15.60
) has
shown promising effects in the treatment of schizophrenia and AD, and partial agonists may have
therapeutic advantages as compared to full antagonists in terms of fewer side effects. A number
of glycine
B
antagonists have also been developed. L-689,560 (
15.63
) displays high potency, and
is derived from the endogenous compound kynurenic acid (
15.62
), the i rst glycine
B
antagonist
reported (Figure 15.15).
O
HO
NH
N
COOH
COOH
OH
H
2
N
H
2
N
H
2
N
H
2
N
O
O
Glycine (
15.58
)
(
R
)-Serine (
15.59
)
(
R
)-Cycloserine (
15.60
)
(
R
)-HA-966 (
15.61
)
O
HN
OH
Cl
H
N
Cl
COOH
H
COOH
Kynurenic acid (
15.62
)
L-689, 560 (
15.63
)
FIGURE 15.15
Structures of glycine (
15.58
) and an agonist (
15.59
), two partial agonists (
15.60
and
15.61
)
and two antagonists (
15.62
and
15.63
) at the glycine
B
receptor on the NMDA receptor complex.
15.7.5 AMPA R
ECEPTOR
A
GONISTS
A large number of selective and potent AMPA receptor agonists have been developed by substi-
tuting a heterocyclic bioisosteric group for the distal carboxylate group of Glu. For example, the
heterocycles 1,2,4-oxadiazole-3,5-dione, 3-isoxazolol, and uracil, as represented by quisqualic
acid (
15.64
), AMPA (
15.65
), and (
S
)-willardiine (
15.66
), respectively, have been incorporated into
numerous AMPA receptor agonists. The natural product quisqualic acid (
15.64
) was the i rst ago-
nist in use for pharmacological characterization of AMPA receptors, but due to nonselective action
it was later replaced by AMPA (
15.65
).
