Biomedical Engineering Reference
In-Depth Information
O
O
O
O
HO
HO
O
HO
OH
N
N
NH
H
2
N
H
2
N
O
NH
H
2
N
O
N
O
O
Quisqualic acid (
15.64
)
AMPA (
15.65
)
(
S
)-Willardiine (
15.66
)
O
O
O
O
HO
HO
HO
OH
OH
O
N
H
2
N
HN
H
2
N
Br
N
N
O
O
OH
(
S
)-Br-HIBO (
15.67
)
ACPA (
15.68
)
5-HPCA (
15.69
)
FIGURE 15.16
Structures of AMPA (
15.65
) and some AMPA receptor agonists.
The isoxazole-based Glu homolog (
S
)-Br-HIBO (
15.67
) also shows AMPA receptor subtype
selectivity, preferring GluR1 over GluR3 in receptor-binding and functional assays. Replacing
the 3-isoxazolol group of AMPA by a 3-carboxyisoxazole unit gives the Glu homolog ACPA
(
15.68
), which is a selective AMPA receptor agonist that is more potent than AMPA. The
potent excitatory AMPA receptor activity of ACPA (
15.68
) has been shown to reside with the
S
-enantiomer.
Conformational restriction of the skeleton of Glu has played an important role in the design of
selective GluR ligands. However, only few structurally rigid AMPA receptor-selective Glu analogs
have been reported. One such example is the cyclized analog of AMPA, 5-HPCA (
15.69
), which
recently has been resolved. Interestingly, the pharmacological effects of 5-HPCA (
15.69
) reside
exclusively with the
R
-enantiomer, in striking contrast to the usual stereoselectivity trend among
AMPA receptor agonists (Figure 15.16).
15.7.6 C
OMPETITIVE
AND
N
ONCOMPETITIVE
AMPA R
ECEPTOR
A
NTAGONISTS
Early pharmacological studies on AMPA and KA receptors were hampered by the lack of
selective and potent antagonists. The discovery of the quinoxaline-2,3-diones CNQX (
15.70
)
and DNQX (
15.71
) was a breakthrough since these compounds are quite potent antagonists,
although nonselective. Subsequently, the more potent analog NBQX (
15.72
) was shown to be
n eu r o p r o t e c t ive i n c e r eb r a l i s ch em ia a nd t o h ave i m p r ove d A M PA r e c e p t o r s ele c t iv it y c om p a r e d
to CNQX (
15.70
). However, NBQX (
15.72
) failed in clinical trials because of nephrotoxicity
due to a limited aqueous solubility, but nonetheless has become a valuable tool for research.
DNQX (
15.71
) has played a key role in elucidating the binding mode of competitive antagonists,
as it was the i rst antagonist cocrystallized with the GluR2 ligand-binding domain. Attempts
to improve the aqueous solubility of such antagonists without losing activity at AMPA recep-
tors, by introducing appropriate polar substituents onto the quinoxaline-2,3-dione ring system
have been highly successful, and have resulted in very potent AMPA receptor antagonists, as
exemplii ed by ZK200775 (
15.73
).
Another series of potent and selective competitive AMPA receptor antagonists based on the
isantin oxime skeleton includes NS 1209 (
15.74
), which shows long-lasting neuroprotection in ani-
mal models of ischemia and an increased aqueous solubility compared to NBQX (
15.72
). At least
two classes of amino acid-containing compounds, based on decahydroisoquinoline-3-carboxylic
