Biomedical Engineering Reference
In-Depth Information
HOOC
PO
3
H
2
H
2
N
H
2
N
HN
PO
3
H
2
PO
3
H
2
HOOC
HOOC
(
R
)-APV (
15.47
)
CGP 39653 (
15.48
)
CGS19755 (
15.49
)
N
N
N
H
HOOC
HOOC
NH
PO
3
H
2
HN
HN
H
LY233053 (
15.51
)
LY235959 (
15.50
)
FIGURE 15.13
Structures of some competitive NMDA receptor antagonists.
15.7.3 U
NCOMPETITIVE
AND
N
ONCOMPETITIVE
NMDA R
ECEPTOR
A
NTAGONISTS
The dissociative anesthetics PCP (
15.52
) and ketamine (
15.53
) block the NMDA receptor chan-
nel in a use-dependent manner. Thus, initial agonist activation of the channel is a prerequisite in
order for such uncompetitive antagonists to gain access to the binding site, which is situated within
the ion channel. The antagonists eventually become trapped within the ion channel and this may
result in very slow kinetics. MK-801 (
15.54
) has been developed as a very effective uncompeti-
tive NMDA antagonist and has been extensively investigated to probe the therapeutic utility of
such compounds, notably for the treatment of ischemic insults such as, stroke. MK-801 (
15.54
)
and related high-afi nity ligands have, however, shown severe side effects, including psychotomimetic
effects, neuronal vacuolization, and impairment of learning and memory. Ligands with lower afi n-
ity, such as memantine (
15.55
), have shown improved therapeutic indexes. Memantine (
15.55
) is
being used in the treatment of AD and Parkinson's disease, and may also have potential in the
treatment of AIDS dementia. The fast kinetics and low afi nity of memantine (
15.55
) compared to
MK-801 (
15.54
) may explain the absence of severe side effects (Figure 15.14).
Several compounds with noncompetitive activity at NMDA receptors have been described, and these
compounds most likely do not bind to the same site as the uncompetitive ligands. Ifenprodil (
15.56
)
Cl
CH
3
NH
2
N
NH
O
NH
PCP (
15.52
)
Ketamine (
15.53
)
MK-801 (
15.54
)
Memantine (
15.55
)
OH
OH
OH
N
N
HO
HO
Ifenprodil (
15.56
)
CP-101, 606 (
15.57
)
FIGURE 15.14
Structures of some uncompetitive (
15.52
-
15.55
) and noncompetitive (
15.56
and
15.57
)
NMDA receptor antagonists.
