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PDBsum entry 4lz5
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Transport protein
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PDB id
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4lz5
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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 and characterization of a novel dihydroisoxazole class of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic acid (ampa) receptor potentiators.
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Authors
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N.C.Patel,
J.Schwarz,
X.J.Hou,
D.J.Hoover,
L.Xie,
A.J.Fliri,
R.J.Gallaschun,
J.T.Lazzaro,
D.K.Bryce,
W.E.Hoffmann,
A.N.Hanks,
D.Mcginnis,
E.S.Marr,
J.L.Gazard,
M.Hajós,
R.J.Scialis,
R.S.Hurst,
C.L.Shaffer,
J.Pandit,
C.J.O'Donnell.
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Ref.
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J Med Chem, 2013,
56,
9180-9191.
[DOI no: ]
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PubMed id
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Abstract
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Positive allosteric modulators ("potentiators") of
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR)
enhance excitatory neurotransmission and may improve the cognitive deficits
associated with various neurological disorders. The dihydroisoxazole (DHI)
series of AMPAR potentiators described herein originated from the identification
of 7 by a high-throughput functional activity screen using mouse embryonic stem
(mES) cell-derived neuronal precursors. Subsequent structure-based drug design
using X-ray crystal structures of the ligand-binding domain of human GluA2 led
to the discovery of both PF-04725379 (11), which in tritiated form became a
novel ligand for characterizing the binding affinities of subsequent AMPAR
potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to
explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided
16a, a functionally potent compound lacking the potentially bioactivatable
aniline within 8a, but retaining desirable in vitro ADME properties.
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