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PDBsum entry 5i2n
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Transport protein
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PDB id
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5i2n
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References listed in PDB file
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Key reference
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Title
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Discovery of glun2a-Selective nmda receptor positive allosteric modulators (pams): tuning deactivation kinetics via structure-Based design.
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Authors
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M.Volgraf,
B.D.Sellers,
Y.Jiang,
G.Wu,
C.Q.Ly,
E.Villemure,
R.M.Pastor,
P.W.Yuen,
A.Lu,
X.Luo,
M.Liu,
S.Zhang,
L.Sun,
Y.Fu,
P.J.Lupardus,
H.J.Wallweber,
B.M.Liederer,
G.Deshmukh,
E.Plise,
S.Tay,
P.Reynen,
J.Herrington,
A.Gustafson,
Y.Liu,
A.Dirksen,
M.G.Dietz,
Y.Liu,
T.M.Wang,
J.E.Hanson,
D.Hackos,
K.Scearce-Levie,
J.B.Schwarz.
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Ref.
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J Med Chem, 2016,
59,
2760-2779.
[DOI no: ]
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PubMed id
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Abstract
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The N-methyl-d-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable
ionotropic glutamate receptor that is activated by the coagonists glycine and
glutamate. NMDARs are critical to synaptic signaling and plasticity, and their
dysfunction has been implicated in a number of neurological disorders, including
schizophrenia, depression, and Alzheimer's disease. Herein we describe the
discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs)
starting from a high-throughput screening hit. Using structure-based design, we
sought to increase potency at the GluN2A subtype, while improving selectivity
against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
(AMPARs). The structure-activity relationship of channel deactivation kinetics
was studied using a combination of electrophysiology and protein
crystallography. Effective incorporation of these strategies resulted in the
discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective
NMDAR PAM suitable for in vivo characterization.
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