Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity
| Autor: | Dirk Schepmann, Elena Bechthold, Guiscard Seebohm, Cristina García, Freddy A. Bernal, Kirstin Lehmkuhl, Constantin G. Daniliuc, Bastian Frehland, Julian A. Schreiber, Thomas J. Schmidt, Bernhard Wünsch, Inés Alvarez |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular medicine.drug_class Stereochemistry Stereoisomerism Crystallography X-Ray Antiviral Agents Receptors N-Methyl-D-Aspartate 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Piperidines Drug Discovery medicine Ifenprodil Humans Receptor 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Molecular Structure Absolute configuration COVID-19 Biological activity Receptor antagonist Antifibrinolytic Agents Idiopathic Pulmonary Fibrosis COVID-19 Drug Treatment 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry NMDA receptor Molecular Medicine Enantiomer |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01912 |
| Popis: | Ifenprodil (1) is a potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonist that is used as a cerebral vasodilator and has been examined in clinical trials for the treatment of drug addiction, idiopathic pulmonary fibrosis, and COVID-19. To correlate biological data with configuration, all four ifenprodil stereoisomers were prepared by diastereoselective reduction and subsequent separation of enantiomers by chiral HPLC. The absolute configuration of ifenprodil stereoisomers was determined by X-ray crystal structure analysis of (1R,2S)-1a and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity, and selectivity over α, σ, and 5-HT receptors were evaluated. (1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity toward GluN2B-NMDA receptors (Ki = 5.8 nM) and high inhibition of ion flux in two-electrode voltage clamp experiments (IC50 = 223 nM). Whereas the configuration did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity. (1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity for GluN2B-NMDA receptors over adrenergic, serotonergic, and σ1 receptors. |
| Databáze: | OpenAIRE |
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