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UBC Theses and Dissertations

Functional characterization of a novel NMDA receptor positive allosteric modulator Li, Victor


The NMDA receptor is a glutamatergic ionotropic receptor key in mediating neuronal plasticity across virtually all synaptic circuits in the brain. An increasing list of neurological disorders have implicated NMDA receptor hypofunction as an integral part of pathogenesis, necessitating the production of NMDA receptor potentiators as therapeutics. To date, most of these attempts have used increased co-agonism at the glycine binding site of NMDA receptors, but this strategy has been plagued by low specificity and efficacy. Specific allosteric modulation of NMDA receptors is an ideal solution, but until recently, no known drugs were capable of doing so. Building off previous work in our lab that discovered a novel family of compounds capable of modulating NMDA receptor activity through its apical N-terminal domain, we identified and characterized a drug candidate, Npam59, predicted to potentiate both GluN2A- and 2B-containing NMDA receptors. Npam59 was shown to potentiate NMDA currents mediated by both subtypes with EC50 in the low-micromolar range. Npam59 also potentiated d-amphetamine-induced dopamine release in the ventral striatum in an NMDA receptor-dependent manner, but had no observable effect when administered alone. Finally, Npam59 potentiated d-amphetamine-induced hyperlocomotion in Sprague-Dawley rats. These results demonstrate that Npam59 can potentiate the function of NMDA receptors, including both GluN2A- and 2B-containing ones, suggesting its potential as a research tool and drug candidate for further development. Npam59 is the first known NMDA receptor allosteric potentiator with specificity for both GluN2A and GluN2B. Its characterization provides the foundation for therapeutic development and novel insights into the interaction of dopamine-glutamate signaling in the ventral striatum.

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