NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory

Nov 4, 2017The international journal of neuropsychopharmacology

NYX-2925 is a new drug that targets NMDA receptors and influences brain changes linked to learning and memory

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Abstract

NYX-2925 has a therapeutic index of >1000 and a cerebrospinal fluid half-life of 1.2 hours.

NYX-2925 exhibits low potential for off-target activity, showing no significant affinity for various neuroactive receptors.
It enhances N-methyl-D-aspartate receptor activity and long-term potentiation in rat hippocampal slices at concentrations of 100-500 nM.
Single dose ex vivo studies indicate increased metaplasticity and structural plasticity in a hippocampal long-term potentiation paradigm 24 hours post-administration.
Learning enhancement was observed in novel object recognition and positive emotional learning tasks at doses of 0.01-1 mg/kg.
The effects on learning were blocked by the N-methyl-D-aspartate receptor antagonist CPP.

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BACKGROUND: N-methyl-D-aspartate receptors are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro-β-lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known N-methyl-D-aspartate receptor agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid, or ifenprodil.

METHODS: The in vitro and in vivo pharmacological properties of NYX-2925 were examined.

RESULTS: NYX-2925 has a low potential for "off-target" activity, as it did not exhibit any significant affinity for a large panel of neuroactive receptors, including hERG receptors. NYX-2925 increased MK-801 binding to human N-methyl-D-aspartate receptor NR2A-D subtypes expressed in HEK cells and enhanced N-methyl-D-aspartate receptor current and long-term potentiation (LTP) in rat hippocampal slices (100-500 nM). Single dose ex vivo studies showed increased metaplasticity in a hippocampal LTP paradigm and structural plasticity 24 hours after administration (1 mg/kg p.o.). Significant learning enhancement in both novel object recognition and positive emotional learning paradigms were observed (0.01-1 mg/kg p.o.), and these effects were blocked by the N-methyl-D-aspartate receptor antagonist CPP. NYX-2925 does not show any addictive or sedative/ataxic side effects and has a therapeutic index of >1000. NYX-2925 (1 mg/kg p.o.) has a cerebrospinal fluid half-life of 1.2 hours with a Cmax of 44 nM at 1 hour.

CONCLUSIONS: NYX-2925, like rapastinel, activates an NMDA receptor-mediated synaptic plasticity process and may have therapeutic potential for a variety of NMDA receptor-mediated central nervous system disorders.

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NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory

Abstract

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