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6. TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window

Author

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

13. Primary structure of mannuronate lyases SP1 and SP2 fromTurbo cornutusand involvement of the hydrophobic C-terminal residues in the protein stability

Author

Muramatsu, Tsuyoshi, Komori, Kenji, Sakurai, Narumi, Yamada, Koji, Awasaki, Yasuyuki, Fukuda, Kazumasa, and Oda, Tatsuya

Abstract

The complete amino acid sequences of two isoforms, SP1 and SP2, of mannuronate lyase from a wreath shell,Turbo cornutus, were determined to elucidate amino acid residues responsible for causing the more stable protein conformation of SP2. The sequences of the two isoforms were identical except for two hydrophobic C-terminal amino acid residues of SP2, Ile and Leu, which were additionally attached to Thr of the C-terminal residue of SP1 (253 residues in total). The molecular weight of SP2 was calculated to be 28,912 from the amino acid sequence data. Two disulfide bond cross-linkages were found to be between 106 and 115 and between 145 and 150, and a partially buried single SH group was located at 236. A carbohydrate chain that consisted of 3 GlcNAc, 3 Fuc, and 1 Man was anchored on Asn-105 in a typical carbohydrate-binding motif of Asn-X-Ser. This is the first evidence of the primary structure of mannuronate lyase, and no significant homology of the amino acid sequence among other proteins was found. The C-terminal truncated SP2, which was produced by digestion with carboxypeptidase Y and corresponded structurally to SP1, showed a thermal stability identical to that of SP1. These results indicate that the higher stability of SP2 than SP1 arises from the presence of the C-terminal two hydrophobic amino acid residues.

Published
1996
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