J.A. Schreiber, D. Schepmann, B. Frehland, S. Thum, M. Datunashvili, T. Budde, M. Hollmann, N. Strutz-Seebohm, B. Wünsch, and G. Seebohm (2019).
A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors.
Communications Biology 2: 420.
doi: 10.1038/s42003-019-0645-6
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.