Biomedical Engineering Reference
In-Depth Information
H
3
CO
O
O
N
Cl
N
N
N
O
NH
H
2
NO
2
S
S
N
OO
Aniracetam (
15.79
)
CTZ (
15.80)
CX-516 (
15.81
)
N
O
S
O
O
H
LY395153 (
15.82
)
FIGURE 15.18
Structures of some positive allosteric modulators of AMPA receptors.
15.7.8 K A R
ECEPTOR
A
GONISTS
AND
A
NTAGONISTS
The pharmacology and pathophysiology of KA receptors are far less well understood than for
AMPA receptors. However, identii cation of selective agonists and competitive antagonists has
developed the i eld of KA receptor research during recent years, and has provided insight into
the roles of these receptors in the CNS. For a number of years, KA (
15.83
) and domoic acid
(
15.84
) have been used as standard KA receptor agonists despite their activities at AMPA recep-
tors, characterized by nondesensitizing responses at these receptors. (
S
)-ATPA (
15.85
) and (
S
)-5-
I-willardiine (
15.86
) are more selective KA receptor agonists, and these compounds exhibit some
selectivity for the low-afi nity KA receptor subtype GluR5 compared to GluR6. (
S
)-ATPA (
15.85
)
and (
S
)-5-I-willardiine (
15.86
) are structurally related to potent AMPA agonists discussed in
earlier sections, illustrating that the structural characteristics required for activation of GluR1-4
and GluR5 receptors are quite similar. However, the presence of the relatively bulky and lipophilic
tert
-butyl- or iodo-substituents of these compounds is apparently the major determinant of the
observed receptor selectivity.
Among the four possible stereoisomers of the 4-methyl substituted analog of Glu, only the
2
S
,4
R
-isomer (
15.87
) shows selectivity for KA receptors. Replacement of the 4-methyl group of
(2
S
,4
R
)-Me-Glu (
15.87
) by a range of bulky, unsaturated substituents containing alkyl, aryl, or het-
eroaryl groups has yielded a number of interesting GluR5 receptor-selective compounds including
LY339 43 4 (
15.88
). LY339434 shows approximately a 100-fold selectivity for GluR5 over GluR6 and
no afi nity for GluR1, 2, or 4 receptors.
Whereas a large number of selective competitive AMPA receptor antagonists have been
identii ed, only a few selective KA receptor antagonists have been reported. One of the i rst
reported KA receptor-preferring antagonists was the isantin oxime, NS 102 (
15.89
), which
shows some selectivity toward low afi nity [
3
H]KA sites as well as antagonist effect at homo-
meric GluR6. However, low aqueous solubility has limited the use of NS 102 (
15.89
) as a
pharmacological tool. A number of decahydroisoquinoline-based acidic amino acids, including
LY382 88 4 (
15.90
), have been characterized as competitive GluR5-selective antagonists that
exhibit antinociceptive effects.
More recently, a series of arylureidobenzoic acids have been reported as the i rst compounds
with noncompetitive antagonist activity at GluR5. The most potent ligands, exemplii ed by com-
pound
15.91
, exhibit more than 50-fold selectivity for GluR5 over GluR6 or the AMPA receptor
subtypes (Figure 15.19).
