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Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists
Author(s) -
Börgel Frederik,
Szermerski Marina,
Schreiber Julian A.,
Temme Louisa,
StrutzSeebohm Nathalie,
Lehmkuhl Kirstin,
Schepmann Dirk,
Ametamey Simon M.,
Seebohm Guiscard,
Schmidt Thomas J.,
Wünsch Bernhard
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800214
Subject(s) - enantiomer , chemistry , nmda receptor , hydrogenolysis , stereochemistry , chiral column chromatography , benzazepine , sigma 1 receptor , receptor , agonist , organic chemistry , biochemistry , catalysis
To determine the eutomers of potent GluN2B‐selective N ‐methyl‐ d ‐aspartate (NMDA) receptor antagonists with a 3‐benzazepine scaffold, 7‐benzyloxy‐3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepin‐1‐ols ( S )‐ 2 and ( R )‐ 2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of ( S )‐ 2 and ( R )‐ 2 provided the enantiomeric phenols ( S )‐ 3 and ( R )‐ 3 [3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepine‐1,7‐diol] and methyl ethers ( S )‐ 4 and ( R )‐ 4 . All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee ). The absolute configurations were 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 compound series is the R ‐configured phenol ( R )‐ 3 , displaying high GluN2B affinity ( K i =30 n m ), high inhibition of ion flux (IC 50 =61 n m ), and high cytoprotective activity (IC 50 =93 n m ). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.