Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia

Dysfunctional N-methyl- d-aspartate (NMDA) receptor neurotransmission has been implicated in the pathophysiology of schizophrenia. It is thought that this abnormal functioning can be corrected by increasing availability of the NMDA co-agonist glycine through inhibition of glycine transporter type 1...

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Published in:Neuropharmacology 2012-02, Vol.62 (2), p.1152-1161
Main Authors: Alberati, Daniela, Moreau, Jean-Luc, Lengyel, Judith, Hauser, Nicole, Mory, Roland, Borroni, Edilio, Pinard, Emmanuel, Knoflach, Frederic, Schlotterbeck, Götz, Hainzl, Dominik, Wettstein, Joseph G.
Format: Article
Language:English
Subjects:
Amphetamine
Amphetamine - pharmacology
Animals
CA1 Region, Hippocampal - drug effects
Cell Line
Central Nervous System Stimulants - pharmacology
Cerebrospinal fluid
CHO Cells
Cricetinae
Data processing
Dopamine
Dose-Response Relationship, Drug
Glutamate
Glutamatergic transmission
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Glycine
Glycine reuptake inhibitor
Glycine transporter
Hallucinogens - pharmacology
Hippocampus
Humans
Long-term potentiation
Long-Term Potentiation - drug effects
Mental disorders
Mice
Microdialysis
Motor Activity - drug effects
N-Methyl-D-aspartic acid receptors
Neostriatum
Neuropharmacology
Neurotransmission
NMDA
Phencyclidine
Phencyclidine - pharmacology
Piperazines - pharmacology
Pyramidal cells
Rats
Rats, Sprague-Dawley
Schizophrenia
Stress
Sulfones - pharmacology
Synaptic Transmission - drug effects
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Summary:Dysfunctional N-methyl- d-aspartate (NMDA) receptor neurotransmission has been implicated in the pathophysiology of schizophrenia. It is thought that this abnormal functioning can be corrected by increasing availability of the NMDA co-agonist glycine through inhibition of glycine transporter type 1 (GlyT1). Herein is described the pharmacologic profile of RG1678, a potent and noncompetitive glycine reuptake inhibitor. In vitro, RG1678 noncompetitively inhibited glycine uptake at human GlyT1 with a concentration exhibiting half-maximal inhibition (IC 50) of 25 nM and competitively blocked [ 3H]ORG24598 binding sites at human GlyT1b in membranes from Chinese hamster ovary cells. In hippocampal CA1 pyramidal cells, RG1678 enhanced NMDA-dependent long-term potentiation at 100 nM but not at 300 nM. In vivo, RG1678 dose-dependently increased cerebrospinal fluid and striatal levels of glycine measured by microdialysis in rats. Additionally RG1678 attenuated hyperlocomotion induced by the psychostimulant d-amphetamine or the NMDA receptor glycine site antagonist L-687,414 in mice. RG1678 also prevented the hyper-response to d-amphetamine challenge in rats treated chronically with phencyclidine, an NMDA receptor open-channel blocker. In the latter experiment, a decrease in ex vivo striatal [ 3H]raclopride binding was also measured. These data demonstrate that RG1678 is a potent, noncompetitive glycine reuptake inhibitor that can modulate both glutamatergic and dopaminergic neurotransmission in animal experiments that model aspects of schizophrenia. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’. ► In vitro, RG1678 potently, selectively and noncompetitively inhibited human GlyT1. ► RG1678 increased extracellular glycine in rat striatum and cerebrospinal fluid. ► RG1678 attenuated hyperlocomotion induced by an NMDA receptor antagonist in mice. ► RG1678 averted the amphetamine-induced hyper-response of subchronic PCP-treated rats. ► RG1678 may provide benefit to patients with schizophrenia.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2011.11.008