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Commun Biol. 2019 Nov 15;2:420. doi: 10.1038/s42003-019-0645-6. eCollection 2019.

A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors.

Author information

1
1Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, D-48149 Münster, Germany.
2
2Institute of Physiology I, University of Münster, Robert-Koch-Str. 27a, D-48149 Münster, Germany.
3
3Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University Münster, Münster, Germany.
4
4Department of Biochemistry I - Receptor Biochemistry, Ruhr University Bochum, Universitätsstr. 150, D-44801 Bochum, Germany.
5
5Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Robert-Koch-Str. 45, D-48149 Münster, Germany.
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Contributed equally

Abstract

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.

KEYWORDS:

Ligand-gated ion channels; Receptor pharmacology; Structural biology

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