Interactions between glycine transporter type 1 (GlyT-1) and some inhibitor molecules - Glycine transporter type 1 and its inhibitors (Review)

L. Hársing, G. Zsilla, P. Mátyus, K. M. Nagy, B. Marko, Zs Gyarmati, J. Timar

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Glycine is a mandatory positive allosteric modulator of N-methyl-D-aspartate (NMDA)-type ionotropic glutamate receptors in the central nervous system. Elevation of glycine concentrations by inhibition of its reuptake in the vicinity of NMDA receptors may positively influence receptor functions as glycine B binding site on NR1 receptor subunit is not saturated in physiological conditions. Synaptic and extrasynaptic concentrations of glycine are regulated by its type-1 glycine transporter, which is primarily expressed in astroglial and glutamatergic cell membranes. Alteration of synaptic glycine levels may have importance in the treatment of various forms of endogenous psychosis characterized by hypofunctional NMDA receptors. Several lines of evidence indicate that impaired NMDA receptor-mediated glutamatergic neurotransmission is involved in development of the negative (and partly the positive) symptoms and the cognitive deficit in schizophrenia. Inhibitors of glycine transporter type-1 may represent a newly developed therapeutic intervention in treatment of this mental illness. We have synthesized a novel series of N-substituted sarcosines, analogues of the glycine transporter-1 inhibitor NFPS (N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)-propyl] sarcosine). Of the pyridazinone-containing compounds, SzV-1997 was found to be a potent glycine transporter-1 inhibitor in rat brain synaptosomes and it markedly increased extracellular glycine concentrations in conscious rat striatum. SzV-1997 did not exhibit toxic symptoms such as hyperlocomotion, restless movements, respiratory depression, and lethality, characteristic for NFPS. Besides pyridazinone-based, sarcosine-containing glycine transporter-1 inhibitors, a series of substrate-type amino acid inhibitors was investigated in order to obtain better insight into the ligand-binding characteristics of the substrate binding cavity of the transporter.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalActa Physiologica Hungarica
Volume99
Issue number1
DOIs
Publication statusPublished - Mar 1 2012

Fingerprint

Glycine Plasma Membrane Transport Proteins
Glycine
Sarcosine
N-Methyl-D-Aspartate Receptors
Ionotropic Glutamate Receptors
Neurobehavioral Manifestations
Synaptosomes
Poisons
N-Methylaspartate
Synaptic Transmission
Respiratory Insufficiency
Psychotic Disorders
Schizophrenia
Central Nervous System
Binding Sites
Cell Membrane
Ligands
Amino Acids
Brain

Keywords

  • glycine transporter inhibitors
  • glycine transporters
  • pyridazinone-based glycine transporter inhibitors
  • sarcosine-containing glycine transporter inhibitors

ASJC Scopus subject areas

  • Physiology (medical)

Cite this

Interactions between glycine transporter type 1 (GlyT-1) and some inhibitor molecules - Glycine transporter type 1 and its inhibitors (Review). / Hársing, L.; Zsilla, G.; Mátyus, P.; Nagy, K. M.; Marko, B.; Gyarmati, Zs; Timar, J.

In: Acta Physiologica Hungarica, Vol. 99, No. 1, 01.03.2012, p. 1-17.

Research output: Contribution to journalArticle

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