Virginia Research Day 2022

Graduate Student Research Biomedical

03 Pharmacology Of Agonist Concentration Biased NMDA Receptor Modulators: CNS4 & CNS42

Alyssa Ingram; Patrick Rafael; Seth Boehringer; Blaise Costa, PhD Corresponding author: alyssai8@vt.edu

Virginia Tech VCOM Virginia

absorption, and bioavailability (F) of 0.55. Both CNS4 and CNS42 modulate NMDA receptors by novel mechanisms and might improve synaptic strength and neurotransmission. In the future in-vivo studies using animal models of major depression and PTSD will be carried out to further study the benefits of using CNS4 and CNS42 to treat neurological and psychiatric disorders.

based on glutamate concentration. Using electrophysiology of frog oocytes expressing recombinant NMDA receptor subtypes we determined that CNS4 & CNS42 potentiates the GluN1/2D receptor at low glutamate concentration. Based on western blots, sodium and calcium assays carried out using DIV14 rat brain neurons expressing native NMDA receptors, we determined that CNS42 protects neurons from NMDA induced excitotoxicity, and maintains PSD95 expression in cortical and striatal neurons. The pharmacokinetic prediction for drug-like properties reveals oral

N-methyl D-aspartate (NMDA) receptors require precisely controlled synaptic glutamate concentration in order to function normally. Atypical changes in synaptic glutamate homeostasis cause divergent NMDA receptor activity that can lead to neurological and psychiatric disorders, including: schizophrenia, substance abuse, and depression. Therefore, synaptic glutamate-dependent NMDA receptor modulators are needed for the treatment of such disorders. We have characterized two chemically novel compounds, CNS4 and CNS42, which modulate NMDA receptors

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