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

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'.

• Authors: Daniela Alberati, Jean-Luc Moreau, Judith Lengyel, Nicole Hauser, Roland Mory, Edilio Borroni, Emmanuel Pinard, Frederic Knoflach, Götz Schlotterbeck, Dominik Hainzl, Joseph G Wettstein
• Journal: Neuropharmacology (Neuropharmacology) Vol. 62 Issue 2 Pg. 1152-61 (Feb 2012) ISSN: 1873-7064 [Electronic] England
• PMID: 22138164 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• (4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
• Central Nervous System Stimulants
• Hallucinogens
• Piperazines
• Sulfones
• Amphetamine
• Phencyclidine

Topics

• Amphetamine (pharmacology)
• Animals
• CA1 Region, Hippocampal (drug effects)
• CHO Cells
• Cell Line
• Central Nervous System Stimulants (pharmacology)
• Cricetinae
• Dose-Response Relationship, Drug
• Hallucinogens (pharmacology)
• Humans
• Long-Term Potentiation (drug effects)
• Mice
• Motor Activity (drug effects)
• Phencyclidine (pharmacology)
• Piperazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sulfones (pharmacology)
• Synaptic Transmission (drug effects)