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NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes
M Amin Khan1, David R Houck1, Amanda L Gross1
1Aptinyx Inc., Evanston, Ilinois.
The International Journal of Neuropsychopharmacology
|November 4, 2017
Summary
NYX-2925 enhances N-methyl-D-aspartate receptor function, improving synaptic plasticity and learning without adverse effects. This compound shows therapeutic potential for central nervous system disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- N-methyl-D-aspartate (NMDA) receptors are crucial for synaptic plasticity and learning.
- Dysfunction of NMDA receptors is implicated in depression, anxiety, schizophrenia, and neuropathic pain.
- NYX-2925 is a novel spiro-β-lactam compound distinct from known NMDA receptor modulators.
Purpose of the Study:
- To investigate the in vitro and in vivo pharmacological properties of NYX-2925.
- To assess the potential of NYX-2925 as a therapeutic agent for CNS disorders.
Main Methods:
- Evaluated NYX-2925 affinity for neuroactive receptors, including hERG.
- Assessed effects on NMDA receptor binding, current, and long-term potentiation (LTP) in HEK cells and rat hippocampal slices.
- Examined in vivo effects on metaplasticity, structural plasticity, and learning in rodents.
Main Results:
- NYX-2925 demonstrated low off-target activity and no significant affinity for a broad panel of receptors.
- Enhanced NMDA receptor function, LTP, and plasticity at low nanomolar to micromolar concentrations.
- Showed significant learning enhancement in novel object recognition and positive emotional learning paradigms with a therapeutic index >1000.
- Exhibited favorable pharmacokinetic properties, including a CSF half-life of 1.2 hours.
Conclusions:
- NYX-2925 activates NMDA receptor-mediated synaptic plasticity, similar to rapastinel.
- NYX-2925 exhibits a promising safety profile with no observed addictive or sedative effects.
- NYX-2925 holds potential therapeutic value for various central nervous system disorders linked to NMDA receptor dysfunction.
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