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.

中文翻译：

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TAK-137 是一种 AMPA-R 增效剂，几乎没有激动作用，具有广泛的治疗窗。

α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPA-R) 的激活是治疗精神疾病和神经系统疾病的一种有前景的策略，如果钟形反应和狭窄的抗癫痫发作安全边际问题可以被克服。在这里，我们表明 AMPA-R 中 Ser743 的结构干扰是降低含有二氢吡啶并噻二嗪 2,2-二氧化物骨架的 AMPA-R 增效剂的激动作用的关键。凭借这种结构洞察力，TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide 被发现是一种新型 AMPA- R 增效剂在大鼠原代神经元中的激动作用低于 AMPA-R 增效剂 LY451646（(R)-N-（2-（4'-氰基联苯-4-基）丙基）丙烷-2-磺酰胺）。TAK-137 在啮齿动物的神经元中诱导脑源性神经营养因子，并有效改善大鼠和猴子的认知。与 LY451646 相比，TAK-137 对大鼠癫痫发作的安全范围更广。TAK-137 在更广泛的剂量范围内增强了啮齿类动物的神经祖细胞增殖。因此，TAK-137 是一种很有前途的 AMPA-R 增效剂，具有强大的促认知作用和较低的钟形反应和癫痫发作风险。这些数据可能为开发 AMPA-R 增效剂作为精神和神经疾病的治疗药物打开大门。TAK-137 是一种很有前途的 AMPA-R 增效剂，具有强大的促认知作用并降低钟形反应和癫痫发作的风险。这些数据可能为开发 AMPA-R 增效剂作为精神和神经疾病的治疗药物打开大门。TAK-137 是一种很有前途的 AMPA-R 增效剂，具有强大的促认知作用并降低钟形反应和癫痫发作的风险。这些数据可能为开发 AMPA-R 增效剂作为精神和神经疾病的治疗药物打开大门。