NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory
| Autor: | Roger A. Kroes, David R. Houck, Torsten M. Madsen, M. Amin Khan, Patric K. Stanton, Cassia N. Cearley, Amanda L. Gross, Jeffrey Burgdorf, Joseph R. Moskal, Xiao-Lei Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.drug_class Dendritic Spines Emotions Pharmacology Hippocampus Receptors N-Methyl-D-Aspartate Regular Research Articles 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Memory Metaplasticity Rapastinel medicine Ifenprodil Animals Humans Learning Pharmacology (medical) Excitatory Amino Acid Agents Neuronal Plasticity synaptic plasticity Dose-Response Relationship Drug Molecular Structure Chemistry Pyramidal Cells Glutamate receptor Long-term potentiation NMDA receptor Receptor antagonist Rats Psychiatry and Mental health HEK293 Cells 030104 developmental biology Pyrazines Synaptic plasticity Dizocilpine Maleate learning and memory Oligopeptides 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Neuropsychopharmacology |
| ISSN: | 1469-5111 1461-1457 |
| DOI: | 10.1093/ijnp/pyx096 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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