Abstract
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.
Highlights
N-methyl D-aspartate (NMDA) is an analog of the excitatory neurotransmitter L-glutamic acid first synthesized by Jeff Watkins in the early 1960s.1,2 NMDA, with the concurrent binding of the co-agonist D-serine or glycine, selectively activates a specific population of ionotropic glutamate receptors, known as NMDA receptors (NMDARs) that non-selectively conduct monovalent and divalent ions across brain cells at depolarizing membrane potential which unbinds the otherwise-blocking Mg2+ ions
Pulsatile release of glutamate and subsequent changes in glutamate concentration in the synapse are essential for maintaining normal brain physiology.13–18 drugs that modulate NMDARs based on surrounding glutamate concentration could be useful to treat clinical conditions that require enhancing the activity of a subpopulation of receptors that are hypo-activated either because of insufficient glutamate release or rapid uptake or both
We have identified a chemically distinct small molecule (CNS4) that modulates NMDAR function based on subunit composition and agonist concentration
Summary
N-methyl D-aspartate (NMDA) is an analog of the excitatory neurotransmitter L-glutamic acid first synthesized by Jeff Watkins in the early 1960s.1,2 NMDA, with the concurrent binding of the co-agonist D-serine or glycine, selectively activates a specific population of ionotropic glutamate receptors, known as NMDA receptors (NMDARs) that non-selectively conduct monovalent and divalent ions across brain cells at depolarizing membrane potential which unbinds the otherwise-blocking Mg2+ ions. Pulsatile release and subsequent changes in glutamate concentration in the synapse are essential for maintaining normal brain physiology.13–18 Glutamate concentration exceeds 1 mM in the synaptic cleft following an action potential for less than 10 ms and rapidly returns to less than 20 nM between two consecutive release events due to high-affinity glutamate uptake by neurons and glial cells.[17,18] glutamate spillover from the synapse, that occurs during the rapid rise and fall event, causes a glutamate concentration gradient across the penumbra of the synapse, commonly known as the extrasynaptic site This concentration gradient at extrasynaptic sites varies over three orders of magnitude, ranging from 0.02 to 30 μM as identified by electrophysiology and microdialysis experiments.[19,20]. This compound was synthesized and pharmacologically studied for its glutamate concentration-dependent effect on different NMDAR subtypes
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