Publication of the Year 2019
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
Abstract
NMDA receptors of the glutamate receptor family underlie learning and memory formation in vertebrates and are associated with a number of neurodegenerative diseases. Therefore, specific inhibitors of the various heteromeric subunit combinations that constitute functionally divergent isoforms of these receptors are much sought after. Specifically, inhibitors of the variants formed with the glutamate-binding subunits GluN2A through GluN2D are if clinical interest. Ifenprodil has long been recognized as a GluN2B subtype-selective inhibitor, but unfortunately also inter-acts with serotonergic and adrenergic receptors, thus limiting its clinical usefulness. In this study the backbone of ifenprodil was successfully modified in an attempt to reduce such cross-reactivities while retaining high affinity for GluN2B-containing NMDA receptors. Additionally, the binding pocket of ifenprodil as well as its inhibitory mechanism were characterized by in silico simulations.
