Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia.
Neuropharmacology
; 62(2): 1152-61, 2012 Feb.
Article
en En
| MEDLINE
| ID: mdl-22138164
ABSTRACT
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 [(3)H]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 [(3)H]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'.
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1
Banco de datos:
MEDLINE
Asunto principal:
Piperazinas
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Sulfonas
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Potenciación a Largo Plazo
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Transmisión Sináptica
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Región CA1 Hipocampal
Límite:
Animals
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Humans
Idioma:
En
Revista:
Neuropharmacology
Año:
2012
Tipo del documento:
Article
País de afiliación:
Suiza