9GIB

NMDA bound to compound 380

This is a non-PDB format compatible entry.

Summary for 9GIB

• Entry DOI: 10.2210/pdb9gib/pdb
• Related: 9GIG
• Descriptor: Glutamate receptor, Isoform 1 of Glutamate receptor ionotropic, NMDA 1, GLYCEROL, ... (7 entities in total)
• Functional Keywords: ion transport ligand gated ion channel, transport protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 2
• Total formula weight: 65861.00

Authors

Carr, K.H.,Ascic, E.,Leonard, P.M. (deposition date: 2024-08-19, release date: 2024-11-27, Last modification date: 2024-12-11)

Primary citation

Ascic, E.,Marigo, M.,David, L.,Frisch Herrik, K.,Grupe, M.,Hougaard, C.,Mork, A.,Jones, C.R.,Badolo, L.,Frederiksen, K.,Boonen, H.C.M.,Jensen, H.S.,Kilburn, J.P.
Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103.
J.Med.Chem., 67:20135-20155, 2024

PubMed Abstract: The discovery of d-cycloserine (), 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 , particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound . This compound acts as a partial agonist of the GluN1/GluN2B complex, exhibiting 24% efficacy, and has an EC value of 78 nM. Subsequent investigations led us to (Lu AF90103), a methyl ester prodrug of capable of penetrating the blood-brain barrier, as confirmed by rat microdialysis studies. In different rat models relevant to neuropsychiatric diseases, administering led to 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.

PubMed: 39560374
DOI: 10.1021/acs.jmedchem.4c01477

Experimental method

X-RAY DIFFRACTION (1.948 Å)