Target Validation Information
Target ID T69685
Target Name Sodium- and chloride-dependent glycine transporter 1
Target Type
Clinical Trial
Drug Potency against Target ALX-5407 Drug Info IC50 = 3 nM [526208]
SSR-504734 Drug Info IC50 = 18 nM [552645]
Org-24461 Drug Info IC50 = 22 nM [553263]
R1678 Drug Info IC50 = 18 nM
Action against Disease Model ALX-5407 ALX 5407, a potent and selective inhibitor of the hGlyT1 glycine transporter, completely inhibited glycine transport in the GlyT1 cells, with an IC(50) value of 3 nM, but had little or no activity at the h uMan GlyT2 transporter, at other binding sites for glycine, or at other neurotransmitter transporters. The inhibition of glycine transport was essentially irreversible. ALX 5407 represents a novel tool in the investigation of N-methyl-D-aspartate-receptor function. This class of drug may lead to novel therapies in the treatment of schizophrenia [526208] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Selective deletion of glycine transporter 1 (GlyT1) in forebrain neurons enhances N-methyl-D-aspartate receptor (NMDAR)-dependent neurotransmission and facilitates associative learning. These effects are attributable to increases in extracellular glycine availability in forebrain neurons due to reduced glycine re-uptake. Using a forebrain- and neuron-specific GlyT1-knockout mouse line (CamKIIalphaCre; GlyT1tm1.2fl/fI), the authors investigated whether this molecular intervention can affect recognition memory. In a spontaneous object recognition memory test, enhanced preference for a novel object was demonstrated in mutant mice relative to littermate control subjects at a retention interval of 2 hr, but not at 2 min. Furthermore, mutants were responsive to a switch inthe relative spatial positions of objects, whereas control subjects were not. These potential procognitive effects were demonstrated against a lack of difference in contextual novelty detection: Mutant and control subjects showed equivalent preference for a novel over a familiar context. Results therefore extend the possible range of potential promnesic effects of specific forebrain neuronal GlyT1 deletion from associative learning to recognition memory and further support the possibility that mnemonic functions can be enhanced by reducing GlyT1 function [526208]
References
Ref 526208Mol Pharmacol. 2001 Dec;60(6):1414-20.ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter.
Ref 552645Progress in the preparation and testing of glycine transporter type-1 (GlyT1) inhibitors. Curr Top Med Chem. 2006;6(17):1883-96.
Ref 526208Mol Pharmacol. 2001 Dec;60(6):1414-20.ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter.
Ref 553263Effects of a neutrophil elastase inhibitor (ONO-5046) on acute pulmonary injury induced by tumor necrosis factor alpha (TNFalpha) and activated neutrophils in isolated perfused rabbit lungs. Am J Respir Crit Care Med. 1998 Jan;157(1):89-94.

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