Glycine Transporter Type-1 and its Inhibitors

Abstract

The ionotropic glutamate receptor NMDA is allosterically modulated by glycine, a coagonist, its presence is an absolute requirement for receptor activation. The transport of glycine in glutamatergic synapse is carried out by glycine transporter-1 (GlyT1), a Na+/Cl(-)-dependent carrier molecule. The primary role of GlyT1 is to maintain glycine concentrations below saturation level at postsynaptic NMDA receptors. Several isoforms of GlyT1 (a-e) have been identified, which are expressed both in glial and neuronal cell membranes. GlyT1 operates bidirectionally: it decreases synaptic glycine concentration when operates in normal mode and releases glycine from glial cells as operates in a reverse mode. It is expected that non-transportable, non-competitive inhibitors of GlyT1 may have therapeutic value in CNS disorders characterized by hypofunctional NMDA receptor-mediated glutamatergic neurotransmission. Accordingly, GlyT1 inhibitors exhibited antipsychotic profile in a number of animal tests. The first promising in vitro and in vivo experiments with glycine itself, and its N-methyl analogue, sarcosine, had initiated the syntheses of potential GlyT1 inhibitors with more complex structures, in which, however, the glycine or sarcosine moiety had always been incorporated. Those attempts led to the development of two compounds, ALX-5407 and Org-24461 with high inhibitory potency; however, none of which is now considered as a drug candidate due, most probably, to safety and/or pharmacokinetic issues. More recently, several structurally new series of highly potent inhibitors with no aminomethylcarboxy group have also been discovered. Some of them might be expected to fulfill all requirements for clinical development. The new generation of GlyT1 inhibitors may represent a novel treatment of patients suffering from schizophrenia and/or other neuropathological conditions.

Synthesis and characterization of [125I]2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide as novel imaging probe for glycine transporter 1

“…8 Unfortunately, none of these compounds are expected to be promising drug candidates because of their safety profiles and pharmacokinetics. 9 More recently, second generation non-amino acid type series of compounds have been developed as potent GlyT1 inhibitors. Some of them showed positive results for clinical use in the treatment of schizophrenia.…”

“…Some of them showed positive results for clinical use in the treatment of schizophrenia. 6,9 In addition, recent reports suggested that GlyT1 inhibitors could be also applied for various disorders such as depression, anxiety, seizures, and neuropathic pain by modulating NMDA receptor or inhibitory GlyRs. 10,11 However, the existence of a correlation between the progress of such diseases and the change of GlyT1 expression and activity remains to be solved.…”

Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

“…Great number of compounds with diverse chemical structures has been reported to inhibit GlyT-1 activity [15,16]. A major effort has been made to find selective and potent inhibitors of GlyT-1 with pharmacological profile suitable for clinical drug development.…”

Lidocaine Metabolites Inhibit Glycine Transporter 1

“…MEGX shows about 80% potency of the parent drug at voltage-dependent sodium channels, while GX and EG are nearly ineffective. Based on structural similarities to the alternative GlyT1 substrate sarcosine, 22 lidocaine metabolites might also affect GlyT1 function. This hypothesis would explain most of the antinociceptive effects of systemic lidocaine application in neuropathic pain.…”