# Selective Modulation of the GluN2B/C/D Containing N‑Methyl‑d‑Aspartate Receptors: A New Frontier in Targeted Neurotherapeutics

## TL;DR

Scientists are developing new drugs that selectively target specific NMDAR subunits to treat neurological disorders like autism and depression.

## Contribution

A new series of subunit-selective positive allosteric modulators for GluN2B/C/D NMDARs with high potency and selectivity was identified.

## Key findings

- A series of GluN2B/C/D-biased PAMs was developed with 20-fold increased potency.
- Structure–activity relationship optimization enabled high subunit selectivity.
- These findings offer insights for targeted NMDAR drug development.

## Abstract

N-methyl-d-aspartate receptors
(NMDARs)
are a class of ionotropic glutamate receptors that mediate synaptic
plasticity and excitatory neurotransmission throughout the central
nervous system (CNS). Dysregulation of NMDAR function has been implicated
in multiple neurological disorders such as autism, schizophrenia,
and depression. Thus, NMDARs are considered crucial therapeutic targets,
and extensive studies have focused on the development of NMDAR modulators.
Positive allosteric modulators (PAMs) represent a promising approach
to regulate NMDARs hypofunction; however, the availability of subunit-selective
PAMs remains limited. A recent study has identified a series of GluN2B/C/D-biased
PAMs with approximately 20-fold increased potency and high subunit
selectivity through structure–activity relationship (SAR) optimization,
which provides valuable insights for NMDARs-targeted drug development.