1. TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window
- Author
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Kunugi, Akiyoshi, Tanaka, Maiko, Suzuki, Atsushi, Tajima, Yasukazu, Suzuki, Noriko, Suzuki, Motohisa, Nakamura, Shinji, Kuno, Haruhiko, Yokota, Akihiro, Sogabe, Satoshi, Kosugi, Yohei, Awasaki, Yasuyuki, Kaku, Tomohiro, and Kimura, Haruhide
- Subjects
Neurons ,Pharmacology ,Mice, Inbred ICR ,Sulfonamides ,Behavior, Animal ,Brain-Derived Neurotrophic Factor ,Primary Cell Culture ,Haplorhini ,Article ,Cell Line ,Mice, Inbred C57BL ,Rats, Sprague-Dawley ,Psychiatry and Mental health ,Cognition ,Neural Stem Cells ,Seizures ,Animals ,Rats, Long-Evans ,Excitatory Amino Acid Agents ,Receptors, AMPA ,Cell Proliferation - Abstract
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.
- Published
- 2018