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

Abstract

The number of N-Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer’s disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options. Current medications are nonselective and can lead to unwanted side effects in patients. A promising therapeutic approach is the targeted inhibition of NMDARs in the brain. NMDARs containing different subunits and splice variants display different physiological properties and play a crucial role in learning and memory, as well as in inflammatory or injury processes. They become overactivated during the course of the disease, leading to nerve cell death. Until now, there has been a lack of understanding of the general functions of the receptor and the mechanism of inhibition, which need to be understood in order to develop inhibitors. Ideal compounds should be highly targeted and even splice-variant-selective. However, a potent and splice-variant-selective NMDAR-targeting drug has yet to be developed. Recently developed 3-benzazepines are promising inhibitors for further drug development. The NMDAR splice variants GluN1-1b-4b carry a 21-amino-acid-long, flexible exon 5. Exon 5 lowers the NMDAR’s sensitivity to allosteric modulators by probably acting as an NMDAR modulator itself. The role of exon 5 in NMDAR modulation is still poorly understood. In this review, we summarize the structure and pharmacological relevance of tetrahydro-3-benzazepines.

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases

“…NP10679, developed by NeurOp Inc. in Atlanta, GA, USA, is designed to counteract minor changes in extracellular pH that happen during conditions such as strokes and traumatic brain injuries. It is noteworthy that extracellular protons can strongly inhibit NMDARs, impacting the activity of NMDARs containing the GluN2B subunit [102,103]. Nerinetide, alternatively referred to as NA-1 or Tat-NR2B9c, is a peptide composed of the Tat sequence followed by the last nine C-terminal residues of the NMDAR-GluN2B subunit, which contains the PDZ ligand.…”