Advancements\nin NMDA Receptor-Targeted Antidepressants:\nFrom d‑Cycloserine Discovery to Preclinical Efficacy\nof Lu AF90103

The discovery of d-cycloserine\n(<b>DCS</b>), a partial\nagonist of the NMDA receptor that exhibits antidepressant effects\nwithout the psychotomimetic effects of ketamine, has fueled interest\nin new NMDA-targeting antidepressants. Our objective was to identify\npotent partial agonists mirroring <b>DCS</b>, particularly tailored\nfor the GluN2B subtype of the NMDA receptor. Through a structure-based\ndrug design approach, we discovered compound <b>42d</b>. This\ncompound acts as a partial agonist of the GluN1/GluN2B complex, exhibiting\n24% efficacy, and has an EC<sub>50</sub> value of 78 nM. Subsequent\ninvestigations led us to <b>42e</b> (Lu AF90103), a methyl ester\nprodrug of <b>42d</b> capable of penetrating the blood–brain\nbarrier, as confirmed by rat microdialysis studies. In different rat <i>in vivo</i> models relevant to neuropsychiatric diseases, administering <b>42e</b> led to <b>42d</b> demonstrating both acute effects,\nobserved in a seizure model and EEG, and lasting effects in the stress-sensitive\nhippocampal pathway and an antidepressant-sensitive model.