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Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists.
- Source :
-
ChemMedChem [ChemMedChem] 2018 Aug 10; Vol. 13 (15), pp. 1580-1587. Date of Electronic Publication: 2018 Jul 04. - Publication Year :
- 2018
-
Abstract
- 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-1H-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-1H-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 <subscript>i</subscript> =30 nm), high inhibition of ion flux (IC <subscript>50</subscript> =61 nm), and high cytoprotective activity (IC <subscript>50</subscript> =93 nm). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.<br /> (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Chromatography, High Pressure Liquid methods
Circular Dichroism
Drug Evaluation, Preclinical
Electrochemical Techniques instrumentation
Electrochemical Techniques methods
Electrodes
Humans
Mice
Stereoisomerism
Excitatory Amino Acid Antagonists chemical synthesis
Excitatory Amino Acid Antagonists pharmacology
Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 13
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 29806151
- Full Text :
- https://doi.org/10.1002/cmdc.201800214