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

  • J Med Chem. 2024 Nov 28;67(22):20135-20155. doi: 10.1021/acs.jmedchem.4c01477.
Erhad Ascic  1 ,  Mauro Marigo  1 ,  Laurent David  1 ,  Kjartan Frisch Herrik  1 ,  Morten Grupe  1 ,  Charlotte Hougaard  1 ,  Arne Mørk  1 ,  Christopher R Jones  1 ,  Lassina Badolo  1 ,  Kristen Frederiksen  1 ,  Harrie C M Boonen  1 ,  Henrik Sindal Jensen  1 ,  John Paul Kilburn  1
Affiliations
  • 1. Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, 9 Ottiliavej, Valby, DK-2500 Copenhagen, Denmark.
PMID: 39560374 DOI: 10.1021/acs.jmedchem.4c01477
Abstract

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.

Products