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PDBsum entry 4u4x
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Membrane protein
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PDB id
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4u4x
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References listed in PDB file
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Key reference
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Title
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Positive allosteric modulators of 2-Amino-3-(3-Hydroxy-5-Methylisoxazol-4-Yl)propionic acid receptors belonging to 4-Cyclopropyl-3,4-Dihydro-2h-1,2,4-Pyridothiadiazine dioxides and diversely chloro-Substituted 4-Cyclopropyl-3,4-Dihydro-2h-1,2,4-Benzothiadiazine 1,1-Dioxides.
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Authors
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P.Francotte,
A.B.Nørholm,
T.Deva,
L.Olsen,
K.Frydenvang,
E.Goffin,
P.Fraikin,
P.De tullio,
S.Challal,
J.Y.Thomas,
F.Iop,
C.Louis,
I.Botez-Pop,
P.Lestage,
L.Danober,
J.S.Kastrup,
B.Pirotte.
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Ref.
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J Med Chem, 2014,
57,
9539-9553.
[DOI no: ]
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PubMed id
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Abstract
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Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive
allosteric modulators were cocrystallized with the GluA2 ligand binding domain
in order to decipher the impact of the position of the nitrogen atom on their
binding mode at the AMPA receptors. The latter was found to be very similar to
that of previously described benzothiadiazine-type AMPA receptor modulators. The
affinity of the two compounds for the receptor was determined by isothermal
titration calorimetry. Accordingly, the synthesis and biological evaluation of
novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and
completed with the synthesis of the corresponding chloro-substituted
4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The
"8-aza" compound 32 was found to be the most potent
pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the
7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine
dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c
was chosen for a more complete preclinical evaluation. The compound was able to
easily cross the blood-brain barrier. In an in vivo object recognition test with
CD1 mice, oral administration of 36c was found to significantly improve
cognition performance at doses as low as 1 mg/kg.
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Secondary reference #1
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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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Secondary reference #2
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Title
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Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor glua2.
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Authors
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C.Krintel,
K.Frydenvang,
L.Olsen,
M.T.Kristensen,
O.De barrios,
P.Naur,
P.Francotte,
B.Pirotte,
M.Gajhede,
J.S.Kastrup.
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Ref.
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Biochem J, 2012,
441,
173-178.
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PubMed id
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