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Advanced Neurology NMDA receptors in neuropsychiatric diseases

2.4.2. LTD which reduces side effects and off-target. Besides, the

There are also many contradictory results on the LTD inhibition of NAMs is <100%, so partial function of
with the composition of NMDAR subunits. One study NMDARs can be preserved, so as to avoid excessive
suggested that ifenprodil blocks LTD in hippocampus [154] , blockade of receptors. This partial inhibition of NAMs has
while the results of other research groups indicated that a better safety profile than competitive antagonists and
ifenprodil does not affect LTD [159] or even enhances LTD [160] . channel blockers. In schizophrenia caused by NMDAR
Disruption the interaction of GluN2B and PSD95 has no hypofunction, or other cognitive disorders, PAMs only
effect on LTD, although the level of synaptic GluN2B is enhanced the activity of weakly activated NMDAR-
reduced [161] . Moreover, the overexpression of GluN2B does mediated signals to restore normal function. This is unlike
not affect the LTD [162] , while the LTD is deficient in GluN2B the NMDAR agonists, which could activate all receptors
knockout mice and KIF17 knockout mice, due to the and lead to side effects and excitotoxicity. Therefore, a
reduction of synaptic GluN2B [93,146] . Thus, these conflicting better understanding of these allosteric modulators can
findings point to the ambiguous function of the GluN2B improve their usage in clinical practice.
subunit in LTD, and to the fact that the experimental 2.5.1. The antagonists of NMDARs
conditions are important for the induction of LTD.
The previous studies have shown that most NMDAR
On the other hand, some studies found that NVP-
AAM077 not only impaired LTP but also blocked LTD [155,163] . antagonists basically interact with NMDARs by glutamate
binding site, glycine binding sites, NTD binding sites,
By contrast, the NVP-AAM077 only affected LTP but or ion channel pores. The glutamate is an activator of
did not impair LTD in slices [154] or in vivo [164] . Besides,
overexpression GluN2A induced decreased LTD [152] and NMDARs. Agonists and antagonists that interact with
[56]
GluN2A knockout mice displayed no impairment of glutamate binding sites were first identified , such as
LTD [165] . However, the LTD could be induced by the 0.5 Hz D-α-amino adipic acid and D-AP5. Since glutamate
stimulation in GluN2A knockout mice [165] . binding affinity is the strongest in GluN2D followed by
GluN2B/2C, and the lowest in GluN2A, the competitive
More experiments are warranted to clarify the role of antagonists generally have the strongest inhibition on
NMDAR subunits in the LTD. GluN2A, then on GluN2B/2C. For example, CPP is more
sensitive to GluN2A subunit than to other subunits [173] .
2.5. NMDARs pharmacology
Quinoxalinedione derivative (1RS,1’S)-PEAQX, a GluN2A
NMDARs play a role in the neuropsychiatric disorders. competitive antagonist, has no effect on GluN2B [174] .
The dysfunction of NMDARs involved in many disease, At present, the NVP-AAM077 ([1R,1’S]-stereoisomer)
such as AD, Parkinson’s disease (PD), epilepsy, and purified from (1RS,1’S)-PEAQX is widely used to inhibit
schizophrenia [166] . Therefore, in the past decades, a GluN2A-NMDARs.
great deal of money has been spent to develop NMDAR
antagonists and agonists to cure the diseases associated Antagonists against the glycine binding site have
[175,176]
with NMDAR. For example, the ketamine and rapastinel been found . Glycine binds to GluN1 subunit of
(GLYX-13) are used for the treatment of depression [167-169] . NMDARs, so these antagonists show no selectivity for
Memantine, a NMDAR blocker, has been proven for use the subunits. The antagonists that act through glycine site
in treating AD and increasing cognitive behavior of AD include HA-966 [177] , 7-chloro-5-iodokynurenic acid [176] ,
patients [170,171] . Unfortunately, due to the off-target or side L-701,324, [178] and MDL 105,519 [178] .
effects of excessive inhibition of NMDAR, many drugs have The channel sequence and structure of NMDARs are
failed in most clinical trials [166,172] . Despite the challenges, highly conserved, so the selectivity of channel blocker
there are still opportunities to develop NMDAR drugs. is little. The NMDAR blockers, such as ketamine and
Many positive and negative allosteric modulators phencyclidine (PCP), act as the anesthetics that bind
2+
(PAMs and NAMs, respectively) have been found recently. the ion channel pore [179,180] . However, when the Mg are
In addition to the antagonists and agonists of NMDAR, present, the memantine appears to be more sensitive to
the allosteric modulators can positively and negatively GluN1/GluN2C and GluN1/GluN2D receptors. Besides,
regulate the NMDAR activity. Compared with antagonist the MK-801 is also a NMDAR channel blocker, which
or channel blocker, the allosteric modulators have many binds to channel pore when the NMDARs are activated [181] .
potential advantages in therapeutics development. The 2.5.2. NAMs
binding domain of allosteric modulators with NMDARs is
not highly conserved ligand-binding site or channel pore. The binding sites of NMDAR subunits with NAMs are
Therefore, allosteric agents have better subunit selectivity, not a highly conserved ligand binding site or channel

Volume 1 Issue 2 (2022) 7 https://doi.org/10.36922/an.v1i2.148