Page 64 - AN-1-2

Advanced Neurology NMDA receptors in neuropsychiatric diseases

pore, so the subunit-specificity of NAMs is greater than 2.5.3. PAMs
the antagonists. Due to the noncompetitive glutamate The function of PAMs is to enhance the NMDAR function.
and glycine binding site and independent NTD regulation Endogenous PAMs include ATP [193] , histamine [194] , Mg ,
2+
to activity, the NAMs are safer to be used in the clinical polyamines such as spermine [195] , and pregnenolone
settings. Many NAMs have been found in recent years, sulfate (PS) [196] . The enhancement of histamine and ATP
including sulfonamide series, quinazoline-4-one series, is both enhanced at high glutamate concentrations. The
and phenanthroic and naphthaloic acid NAMs. Ifenprodil, low concentrations of ATP can enhance the GluN2A-,
CP101, and RO25 also belong to the category of NAMs.
GluN2B-, and GluN2C-containing NMDARs [193] . The
Ifenprodil was studied in treatment in stroke and then effects of spermine on NMDARs are different; it can either
was proven a GluN1/GluN2B receptor antagonist, which increase the potency of glycine, or allosterically interact
binds the NTD of the subunit [182,183] . Subsequently, CP101, with GluN2B- and GluN1-lacked exon 5, that is, the
606 [184] and Ro 25-6981 [185] were developed as GluN1/ glycine-independent [194,195,197] . PS potentiates GluN2A- and
GluN2B antagonists, which have been studied for clinical GluN2B-containing NMDARs at micromolar
use. concentrations, while inhibits the GluN2C and GluN2D
The TCN-201, one of sulfonamide series, was first found subunits [198] . The mechanism of the potentiation of PS
as a noncompetitive GluN2A NAM [186] , which binds with is the increased open probability of NMDARs through
dimer interface between the LBD . TCN-201 has a higher phosphorylation [199,200] . Similar results have been found
[40]
affinity with GluN2A over other GluN2 subunits [186,187] . by single channels analysis that the frequency of channel
Studies indicated that the TCN-201, which reduces the openings is enhanced by PS [201,202] . Besides, the studies
potency of glycine and D-serine, is a noncompetitive have proven that the S2 domain of GluN2A may be the
antagonist [187,188] . The inhibition of TCN-201 is abolished at interaction site of PS with GluN2A [200] , while the S2 and
high concentrations of glycine [186] . M4 domain of GluN2B play an important role in the
potentiation [203] .
The quinazoline-4-one series inhibitor has been
identified to be more sensitive to GluN2C and GluN2D Other PAMs of NMDARs, such as phenanthrene,
compared with GluN2A and GluN2B [189] . QNZ46, one naphthalene, and coumarin derivatives, have been
of this type of noncompetitive NAMs, exerts differential reported in many studies [204] . UBP512, a phenanthroic
effect on GluN2A and GluN2D. Point mutations and acid, enhanced the GluN2A-contaning NMDAR, but
chimeric molecules were used to identify the binding site not the GluN2B-containing NMDAR, and inhibited the
of QNZ46, and S2 domain of GluN2 is found to be critical GluN2C and GluN2D subunits. The UBP710 enhanced
for QNZ46 activity [190] . Unlike TCN-201, QNZ46 increases both GluN2A- and GluN2B-containing NMDARs, while
the potency of glutamate but not glycine, although inhibited the GluN2C and GluN2D subunits. The UBP551,
QNZ46 is a NAM. The feature of QNZ46 inhibition is a naphthoic acid NMDAR PAM, potentiated the GluN2D
needed in the binding with glutamate. After QNZ46/ subunit, while had no effect on the other three GluN2
glycine preincubation, glutamate plus QNZ46/glycine subunits [191] . Another naphthoic acid NMDAR PAM is the
application produced a transient peak response followed UBP684, which could enhance the effect on all GluN1/
by homeostasis inhibition. Thus, the glutamate binding is GluN2 receptors by increasing the open probability
essential for the inhibition of QNZ46. The QNZ46 inhibits and mean open time [205,206] . The UBP714, a coumarin
NMDAR function by binding in S2, and the binding site of derivative, slightly potentiated the GluN2A, GluN2B
QZN46 with GluN2 is exposed by glutamate binding. and GluN2D [207] . The CIQ is a potentiator of GluN2C- or
GluN2D-containing NMDAR [208,209] . Studied indicated that
Phenanthroic and naphthaloic acid NAMs exhibit
different subunit selectivity and have enhanced or the linker between NTD and LBD and T592 of GluN2D is
[208]
inhibited activity in different subunits. UBP512 not only is the important sites of the GluN2D to activate the CIQ .
a potentiator of GluN2A but also is an inhibitor of GluN2C Recently, the GEN family has been reported as the
and GluN2D-containing NMDARs [191] . Meanwhile, PAMs of GluN2A. According to the analysis of the
the UBP551 showed PAM activity on GluN2D at high GluN2A binding with GEN-6901, we understand that
concentration of 30 μM, but inhibited GluN2A, GluN2B, the V783 of GluN2A is a necessary site for binding with
[38]
and GluN2C subunits at IC50s around 10 μM [191] . Besides, GEN-6901 specifically . The potentiation of GEN-8324,
the UBP618 is an inhibitor of all GluN2 subunits, and instead of GEN-6901, in GluN2A increased the potency of
the CTD is critical for the inhibition [192] . In addition, the glutamate, but both of them had no effect on the sensitivity
UBP608 shows inhibitory effects on GluN2A-NDMA to glycine. Meanwhile, they also decreased the NMDAR
receptor [192] . deactivation . However, there are differences between
[38]

Volume 1 Issue 2 (2022) 8 https://doi.org/10.36922/an.v1i2.148