The discovery of d-cycloserine (DCS), a partial agonist of the NMDA receptor that exhibits antidepressant effects without the psychotomimetic effects of ketamine, has fueled interest in new NMDA-targeting antidepressants. Our objective was to identify potent partial agonists mirroring DCS, particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound 42d. This compound acts as a partial agonist of the GluN1/GluN2B complex, exhibiting 24% efficacy, and has an EC₅₀ value of 78 nM. Subsequent investigations led us to 42e (Lu AF90103), a methyl ester prodrug of 42d capable of penetrating the blood–brain barrier, as confirmed by rat microdialysis studies. In different rat in vivo models relevant to neuropsychiatric diseases, administering 42e led to 42d demonstrating both acute effects, observed in a seizure model and EEG, and lasting effects in the stress-sensitive hippocampal pathway and an antidepressant-sensitive model.

中文翻译：

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NMDA 受体靶向抗抑郁药的进展：从 D-环丝氨酸的发现到 Lu AF90103 的临床前疗效


d-环丝氨酸 （DCS） 是 NMDA 受体的部分激动剂，具有抗抑郁作用，而没有氯胺酮的拟精神病作用，其发现激发了人们对新型 NMDA 靶向抗抑郁药的兴趣。我们的目标是确定反映 DCS 的有效部分激动剂，特别是针对 NMDA 受体的 GluN2B 亚型。通过基于结构的药物设计方法，我们发现了化合物 42d。该化合物充当 GluN1/GluN2B 复合物的部分激动剂，具有 24% 的功效，EC₅₀ 值为 78 nM。随后的调查使我们发现了 42e （Lu AF90103），这是一种能够穿透血脑屏障的 42d 甲酯前药，大鼠微透析研究证实了这一点。在与神经精神疾病相关的不同大鼠体内模型中，施用 42e 导致 42d 表现出在癫痫发作模型和 EEG 中观察到的急性影响，以及在压力敏感的海马通路和抗抑郁药敏感模型中的持久影响。