Downstream allosteric modulation of NMDA receptors by 3-benzazepine derivatives

Abstract

Abstract N-methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR is associated with diseases like Alzheimer’s, Huntington’s, depression and substance addiction. The development of selective receptor modulators therefore constitutes a promising approach for multiple therapeutical applications. Here, we identified (R)- OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of ( R )-OF-NB1 and NMDAR from a biochemical, bioinformatical and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. On the contrary, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of the of its ligand binding domain.