A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors
| Autor: | Maia Datunashvili, Michael Hollmann, Simone Thum, Julian A. Schreiber, Bernhard Wünsch, Guiscard Seebohm, Dirk Schepmann, Bastian Frehland, Thomas Budde, Nathalie Strutz-Seebohm |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemistry Mutagenesis Medicine (miscellaneous) Inhibitory postsynaptic potential Serotonergic General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Structural biology lcsh:Biology (General) Ifenprodil Biophysics Ligand-gated ion channel General Agricultural and Biological Sciences Receptor lcsh:QH301-705.5 030217 neurology & neurosurgery Intracellular |
| Zdroj: | Communications Biology, Vol 2, Iss 1, Pp 1-14 (2019) |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-019-0645-6 |
| Popis: | N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism. Schreiber et al characterize a common inhibitory mechanism for ifenprodil and its derived compounds acting on GluN2B-containing N-methyl-D-aspartate receptors (NMDARs). These insights, generated through mutagenesis of the receptor binding site, chemical modifications of the compounds and structural modeling, may aid in the treatment of neurodegenerative diseases where GluN2B is involved. |
| Databáze: | OpenAIRE |
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