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PDBsum entry 4n07
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Membrane protein
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PDB id
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4n07
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References listed in PDB file
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Key reference
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Title
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Synthesis, Pharmacological and structural characterization, And thermodynamic aspects of glua2-Positive allosteric modulators with a 3,4-Dihydro-2h-1,2,4-Benzothiadiazine 1,1-Dioxide scaffold.
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Authors
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A.B.Nørholm,
P.Francotte,
L.Olsen,
C.Krintel,
K.Frydenvang,
E.Goffin,
S.Challal,
L.Danober,
I.Botez-Pop,
P.Lestage,
B.Pirotte,
J.S.Kastrup.
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Ref.
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J Med Chem, 2013,
56,
8736-8745.
[DOI no: ]
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PubMed id
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Abstract
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Positive allosteric modulators of ionotropic glutamate receptors are potential
compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The
modulators bind within the dimer interface of the ligand-binding domain (LBD)
and stabilize the agonist-bound conformation, thereby slowing receptor
desensitization and/or deactivation. Here we describe the synthesis and
pharmacological testing at GluA2 of a new generation of
3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3
in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by
X-ray crystallography, and the thermodynamics of binding was studied by
isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with
a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the
first time that submicromolar binding affinity has been achieved for this type
of positive allosteric modulator. The major structural factor increasing the
binding affinity of 3 seems to be interactions between the cyclopropyl group of
3 and the backbone of Phe495 and Met496.
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