Biomedical Engineering Reference
In-Depth Information
membrane depolarization in order to relieve a blockade by Mg
2+
. In the normal brain, NMDA
receptors are fundamental to development and function, because of their involvement in synap-
tic plasticity and neuronal signaling processes, including mechanisms of learning and memory.
Furthermore, NMDA receptor-induced neurotoxicity is intimately involved in a number of neu-
ronal disorders as previously mentioned. Functional NMDA receptors are heteromers, typically
consisting of NR1- and NR2-subunits in a tetrameric structure. The Glu-binding site is located on
NR2 subunits and the glycine-binding site on NR1 subunits.
NMDA receptors are unusual among Glu recognition sites inasmuch as the majority of the
more potent ligands, both agonists and antagonists, posses an
R
-coni guration about the
-amino
acid center. NMDA (
15.43
) itself represents the only known agonist in which
N
-methylation does
not lead to reduced afi nity. Other potent NMDA agonists have been developed, particularly by
replacement of the distal acidic group and/or by conformational restriction of the three essen-
tial functional groups, namely, the
α
-acidic moi-
ety. Among the potent NMDA agonists with different distal acidic groups are tetrazolylglycine
(
15.44
) and (
R
)-AMAA (
15.45
), exemplifying two widely used carboxyl bioisosteric groups, the
tetrazole and the 3-isoxazolol, respectively. (
R
)-AMAA (
15.45
) and other Glu ligands have been
developed using the naturally occurring neurotoxin ibotenic acid (
15.46
) as a lead. Ibotenic acid
(
15.46
) is, apart from being a potent NMDA agonist, a potent agonist of some mGluR subtypes and
a somewhat weaker agonist at other Glu receptor types (Figure 15.12).
α
-amino group, the
α
-carboxyl group, and the
ω
CH
3
HN
H
2
N
COOH
HOOC
COOH
HOOC
Glu (
15.2
)
NMDA (
15.43
)
NH
2
H
2
N
HOOC
OH
N
OH
HOOC
H
2
N
N
N
N
N
N
O
O
HOOC
Tetrazolylglycine (
15.44
)
(
R
)-AMAA (
15.45
)
Ibotenic acid (
15.46
)
FIGURE 15.12
Structures of Glu and some NMDA receptor agonists.
15.7.2 C
OMPETITIVE
NMDA R
ECEPTOR
A
NTAGONISTS
A large number of potent and selective competitive NMDA antagonists have been developed, and the
availability of these compounds has greatly facilitated studies of the physiological and pathophysi-
ological roles of NMDA receptors. The distance between the two acidic groups in NMDA antago-
nists is typically one or three C-C bonds longer than in Glu. Many potent ligands have successfully
been developed using
ω
-phosphonic acid analogs, such as (
R
)-APV (
15.47
), as lead structures.
Combination of an
-phosphonate group, a long carbon backbone, and conformational restriction
has led to different series of potent antagonists. Conformational restriction has been achieved by
the use of double bonds (CGP 39653 (
15.48
)), ring systems (CGS19755 (
15.49
), and bicyclic struc-
tures (LY235959 (
15.50
)). These antagonists have shown very effective neuroprotective properties
in various
in vitro
models. However, many of these compounds suffer from poor BBB penetration.
LY233 0 53 (
15.51
) represents another class of antagonists with a tetrazole ring as the terminal acidic
group. Substitution of the tetrazole by a phosphono group has limited effect on the
in vitro
activity
and shows improved bioavailability (Figure 15.13).
ω
