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Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists.
Journal article

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists.

  • Börgel F Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Szermerski M Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Schreiber JA Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Temme L Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Strutz-Seebohm N Myocellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, 48149, Münster, Germany.
  • Lehmkuhl K Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Schepmann D Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Ametamey SM Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Zürich, Switzerland.
  • Seebohm G Myocellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, 48149, Münster, Germany.
  • Schmidt TJ Institut für Pharmazeutische Biologie und Phytochemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Wünsch B Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
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  • 2018-05-29
Published in:
  • ChemMedChem. - 2018
3-benzazepines
GluN2B
NMDA receptors
circular dichroism
cytoprotection
Animals
Chromatography, High Pressure Liquid
Circular Dichroism
Drug Evaluation, Preclinical
Electrochemical Techniques
Electrodes
Excitatory Amino Acid Antagonists
Humans
Mice
Receptors, N-Methyl-D-Aspartate
Stereoisomerism
English 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 (Ki =30 nm), high inhibition of ion flux (IC50 =61 nm), and high cytoprotective activity (IC50 =93 nm). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://susi.usi.ch/global/documents/234276
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