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NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-ß-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory.
Khan, M Amin; Houck, David R; Gross, Amanda L; Zhang, Xiao-Lei; Cearley, Cassia; Madsen, Torsten M; Kroes, Roger A; Stanton, Patric K; Burgdorf, Jeffrey; Moskal, Joseph R.
Affiliation
  • Khan MA; Aptinyx Inc., Evanston, Ilinois.
  • Houck DR; Aptinyx Inc., Evanston, Ilinois.
  • Gross AL; Aptinyx Inc., Evanston, Ilinois.
  • Zhang XL; Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York.
  • Cearley C; Aptinyx Inc., Evanston, Ilinois.
  • Madsen TM; Aptinyx Inc., Evanston, Ilinois.
  • Kroes RA; Aptinyx Inc., Evanston, Ilinois.
  • Stanton PK; Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Ilinois.
  • Burgdorf J; Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York.
  • Moskal JR; Aptinyx Inc., Evanston, Ilinois.
Int J Neuropsychopharmacol ; 21(3): 242-254, 2018 03 01.
Article in En | MEDLINE | ID: mdl-29099938
ABSTRACT

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-ß-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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oligopeptides / Excitatory Amino Acid Agents / Memory / Neuronal Plasticity Type of study: Risk_factors_studies Limits: Animals / Humans / Male Language: En Journal: Int J Neuropsychopharmacol Journal subject: NEUROLOGIA / PSICOFARMACOLOGIA Year: 2018 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oligopeptides / Excitatory Amino Acid Agents / Memory / Neuronal Plasticity Type of study: Risk_factors_studies Limits: Animals / Humans / Male Language: En Journal: Int J Neuropsychopharmacol Journal subject: NEUROLOGIA / PSICOFARMACOLOGIA Year: 2018 Document type: Article