Downstream allosteric modulation of NMDA receptors by 3-benzazepine derivatives

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.

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

“…In terms of safety pharmacology, these modulators must be investigated on common off-targets. (R)-OF-NB1, an optimized 3-benzazepine derived from ifenprodil, can be used as a positive example in drug development, leading to a powerful imaging tool in ALS and potentially other neurodegeneration diseases [68,70,72,73].…”

“…Furthermore, the inhibitory activity of these identified compounds was confirmed on human induced pluripotent stem cell (hiPSC) derived glutamatergic neurons as a physiological test system [59]. (R)-OF-NB1, a WMS-1410 derivative, was established as a selective NMDAR antagonist with significant NMDAR splice variant preference [68]. (R)-OF-NB1 and PF-NB1 were developed successfully as GluN2B-selective and powerful inhibitors (IC 50 for GluN1-1a/GluN2B of 97 nM and 60.9 nM [59,68]), and their application as positron emission tomography (PET) tracers was confirmed [69][70][71][72][73].…”

“…(R)-OF-NB1, a WMS-1410 derivative, was established as a selective NMDAR antagonist with significant NMDAR splice variant preference [68]. (R)-OF-NB1 and PF-NB1 were developed successfully as GluN2B-selective and powerful inhibitors (IC 50 for GluN1-1a/GluN2B of 97 nM and 60.9 nM [59,68]), and their application as positron emission tomography (PET) tracers was confirmed [69][70][71][72][73]. Because of its high blood-brain barrier permeability, 18 F-OF-NB1 builds up in areas of the brain where GluN2B is abundant.…”

“…Since fluorine withdraws electrons, the electron density is reduced at the aromatic ring [77]. The fluorine in (R)-OF-NB1 probably acts through-space by cation-π interaction deactivation at the aromatic ring of GluN1 F113 (Figure 2E) [68].…”