title: 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.affiliation: CNS Discovery, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland. daniela.alberati@roche.com
authors.forename: Daniela
authors.initials: D
authors.lastname: Alberati
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Moreau
authors.forename: Judith
authors.initials: J
authors.lastname: Lengyel
authors.forename: Nicole
authors.initials: N
authors.lastname: Hauser
authors.forename: Roland
authors.initials: R
authors.lastname: Mory
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinard
authors.forename: Frederic
authors.initials: F
authors.lastname: Knoflach
authors.forename: Götz
authors.initials: G
authors.lastname: Schlotterbeck
authors.forename: Dominik
authors.initials: D
authors.lastname: Hainzl
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D016466:CHO Cells; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D010879:Piperazines; D013450:Sulfones; D000661:Amphetamine; D010622:Phencyclidine