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PDBsum entry 5zg0
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Transport protein
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PDB id
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5zg0
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References listed in PDB file
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Key reference
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Title
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Tak-137, An ampa-R potentiator with little agonistic effect, Has a wide therapeutic window.
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Authors
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A.Kunugi,
M.Tanaka,
A.Suzuki,
Y.Tajima,
N.Suzuki,
M.Suzuki,
S.Nakamura,
H.Kuno,
A.Yokota,
S.Sogabe,
Y.Kosugi,
Y.Awasaki,
T.Kaku,
H.Kimura.
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Ref.
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Neuropsychopharmacology, 2019,
44,
961-970.
[DOI no: ]
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PubMed id
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Abstract
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Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor
(AMPA-R) is a promising strategy to treat psychiatric and neurological diseases
if issues of bell-shaped response and narrow safety margin against seizure can
be overcome. Here, we show that structural interference at Ser743 in AMPA-R is a
key to lower the agonistic effect of AMPA-R potentiators containing
dihydropyridothiadiazine 2,2-dioxides skeleton. With this structural insight,
TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine
2,2-dioxide, was discovered as a novel AMPA-R potentiator with a lower agonistic
effect than an AMPA-R potentiator LY451646
((R)-N-(2-(4'-cyanobiphenyl-4-yl)propyl)propane-2-sulfonamide) in rat primary
neurons. TAK-137 induced brain-derived neurotrophic factor in neurons in rodents
and potently improved cognition in both rats and monkeys. Compared to LY451646,
TAK-137 had a wider safety margin against seizure in rats. TAK-137 enhanced
neural progenitor proliferation over a broader range of doses in rodents. Thus,
TAK-137 is a promising AMPA-R potentiator with potent procognitive effects and
lower risks of bell-shaped response and seizure. These data may open the door
for the development of AMPA-R potentiators as therapeutic drugs for psychiatric
and neurological diseases.
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