Advancements in NMDA Receptor-Targeted Antidepressants: From <scp>d</scp>-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103

The discovery of d-cycloserine (<b>DCS</b>), 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 <b>DCS</b>, particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound <b>42d</b>. 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 <b>42e</b> (Lu AF90103), a methyl ester prodrug of <b>42d</b> capable of penetrating the blood-brain barrier, 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, observed in a seizure model and EEG, and lasting effects in the stress-sensitive hippocampal pathway and an antidepressant-sensitive model.