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 Ca 2+ 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.

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Background and purpose: Precisely controlled synaptic glutamate concentration is essential for normal function of the N-methyl D-aspartate (NMDA) receptors expressed in the brain. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration dependent NMDA receptor modulators will be clinically useful agents with less on-target adverse effects. Experimental approach: Two electrode voltage clamp and patch clamp electrophysiology techniques were used for pharmacological characterization. Dynamic Ca2+ and Na+ imaging were performed using cultured rat brain neurons. MTS cell viability assay was used for to study neurotoxicity. Key results: Identified a compound (coded as CNS4) that potentiates NMDA receptor currents based on the glutamate concentration. This compound increases both glycine and glutamate potency, and exhibits no voltage dependent effect. Electrophysiology recordings confirmed agonist concentration dependent changes in peak and steady state currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 mediated region specific disproportionate influx of Na+ compared to Ca2+ in native NMDA receptors. Direct exposure of CNS4 unaltered the viability of cultured cortical or striatal neurons, neither augmented NMDA induced neuronal death. Conclusion and implications: CNS4 is novel in chemical structure, mechanism of action and agonist concentration biased modulatory effect. This compound or its future analogs will be useful for the treatment of brain disorders associated with hypoglutamatergic neurotransmission.