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

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.

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

“…On the contrary, sarcosine, a competitive and transportable substrate type GlyT-1 inhibitor [53] evoked a concentration-dependent elevation of basal [ 3 H]glycine release in the retina. The mode of action of sarcosine to induce [ 3 H]glycine release may fall into the mechanism of heteroexchange, whereby a drug could reverse the direction of a transporter and elicit neurotransmitter release [54].…”

A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice

“…29) Proposed strategies for the treatment of anti-epilepsy via the direct activation of glycine receptors remain controversial but are in progress. 30) GlyT1 inhibitors have been proposed for the treatment of schizophrenia because they can also increase NMDA receptor function in the prefrontal cortex. 31) Sarcosine, another GlyT1 inhibitor, can increase the concentration of extracellular glycine in vivo.…”

Purinergic–Glycinergic Interaction in Neurodegenerative and Neuroinflammatory Disorders of the Retina

“…Recognition of the coagonist role of glycine in glutamate-mediated NMDA receptor activation led to the conclusion that decreases in extracellular glycine concentration may actually result in NMDA receptor hypofunctionality and exert neuroprotection in retinal neurodegenerative disorders. This goal can also be reached by inhibition of the reverse-mode operation of GlyT-1 by its selective inhibitors [15,109]. As shown in Figure 2A, the GlyT-1 inhibitor ACPPB decreased the oxygen-glucose deprivation-induced [ 3 H]glycine release in isolated rat retina and this effect was due to an inhibition of the reverse-mode operation of GlyT-1.…”