Title
Synthesis and pharmacological evaluation of enantiomerically pure GluN2B selective NMDA receptor antagonists
Author
Bernhard Wünsch, Frederik Börgel, Marina Szermerski, Julian A. Schreiber, Louisa Temme, Nathalie Strutz-Seebohm, Kirstin Lehmkuhl, Dirk Schepmann, Simon M. Ametamey, Guiscard Seebohm, Thomas J. Schmidt
Year
2018
Journal
ChemMedChem
Abstract
In order to determine the eutomers of potent GluN2B selective NMDA receptor antagonists with 3‐benzazepine scaffold, benzyl ethers (S)‐2 and (R)‐2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers (S)‐2 and (R)‐2 provided the enantiomeric phenols (S)‐3 and (R)‐3 and methyl ethers (S)‐4 and (R)‐4. All enantiomers were obtained with high enantiomeric purity (ee ≥ 99.7 %). The absolute configuration was determined by CD‐spectroscopy. (R)‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this series of compounds is the (R)‐configured phenol (R)‐3 displaying high GluN2B affinity (Ki = 30 nM), high inhibition of ion flux (IC50 = 61 nM) and high cytoprotective activity (IC50 = 93 ± 39 nM). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.
Instrument
J-815
Keywords
Circular dichroism, Absolute configuration, Pharmaceutical