TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window.
Animals
Behavior, Animal
/ drug effects
Brain-Derived Neurotrophic Factor
/ drug effects
Cell Line
Cell Proliferation
/ drug effects
Cognition
/ drug effects
Excitatory Amino Acid Agents
/ administration & dosage
Haplorhini
Mice, Inbred C57BL
Mice, Inbred ICR
Neural Stem Cells
/ drug effects
Neurons
/ drug effects
Primary Cell Culture
Rats, Long-Evans
Rats, Sprague-Dawley
Receptors, AMPA
/ drug effects
Seizures
/ chemically induced
Sulfonamides
/ pharmacology
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
02
04
2018
accepted:
03
09
2018
revised:
27
08
2018
pubmed:
14
9
2018
medline:
19
12
2019
entrez:
14
9
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30209408
doi: 10.1038/s41386-018-0213-7
pii: 10.1038/s41386-018-0213-7
pmc: PMC6461786
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Excitatory Amino Acid Agents
0
LY 404187
0
Receptors, AMPA
0
Sulfonamides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
961-970Références
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