Journal Article

A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

Bledsoe, Douglas N., Johnston, Tullia V., Mehrkens, Brittney, Costa, Blaise M., Razzaq, Rehan, Vacca, Bryanna N., Klein, Bradley G., Manickam, Dhanasekaran, Kwapisz, Lina Cortés

2021

Overview

Precisely controlled synaptic glutamate concentration is essential for the normal function of the N‐methyl D‐aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration‐dependent NMDA receptor modulators would be clinically useful agents with fewer on‐target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage‐dependent effect. Patch‐clamp electrophysiology recordings confirmed agonist concentration‐dependent changes in maximum inducible currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration‐biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug‐like compounds for the treatment of treatment‐resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission. Novel NMDA receptor modulator selectively potentiates whole‐cell current response based on glutamate concentration.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Allosteric Regulation / Animals / anti‐NMDA receptor encephalopathy / Automation / Benzamides - pharmacology / biased allosteric modulator (BAM) / Brain / Cerebellum - cytology / Cerebral Cortex - cytology / Corpus Striatum - cytology / Dopamine / Dose-Response Relationship, Drug / Experiments / Glutamic Acid - metabolism / HEK293 Cells / Humans / Mental disorders / Mutation / Neurons / Neurons - drug effects / Neurons - metabolism / NMDA receptor / Optical Imaging / Original / Patch-Clamp Techniques / Pharmacology / Piperidines - pharmacology / Rats / Receptors, N-Methyl-D-Aspartate - drug effects / Receptors, N-Methyl-D-Aspartate - metabolism / RNA polymerase / Schizophrenia / Xenopus laevis