Abstract
Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC(50)=150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c.
MeSH terms
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Acetates / chemical synthesis
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Acetates / chemistry
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Acetates / pharmacology
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Amino Acid Transport Systems, Neutral / antagonists & inhibitors*
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Animals
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Antipsychotic Agents / chemical synthesis*
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Antipsychotic Agents / therapeutic use
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Glycine / metabolism
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Glycine Plasma Membrane Transport Proteins
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Hippocampus / drug effects
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Hippocampus / metabolism
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Humans
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Kinetics
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology*
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Rats
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Receptors, N-Methyl-D-Aspartate / drug effects
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Schizophrenia / drug therapy
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Structure-Activity Relationship
Substances
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Acetates
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Amino Acid Transport Systems, Neutral
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Antipsychotic Agents
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Glycine Plasma Membrane Transport Proteins
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Piperazines
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Receptors, N-Methyl-D-Aspartate
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SLC6A9 protein, human
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Slc6a9 protein, rat
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Glycine