org-24598 and Schizophrenia

N-methyl-D-aspartate (NMDA) receptor dysfunction may play a key role in the pathophysiology of schizophrenia. Recent studies have investigated the ability of NMDA/glycine-site modulators to ameliorate persistent negative and cognitive symptoms. Several full or partial glycine-site agonists, including glycine, D-serine and D-cycloserine, have shown effectiveness in small-scale clinical trials. Glycine levels in brain are regulated by GLYT1-type glycine transporters. Recently developed glycine transport inhibitors (GTI) have preclinical behavioral effects similar to those of glycine or D-serine, and may represent a 'next generation' approach to the treatment of the persistent negative and cognitive symptoms of schizophrenia.

Topics: Animals; Glycine; Humans; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40-200 mg/kg) and ORG24598 (0.63-5 mg/kg), the agonists, glycine (40-800 mg/kg), and D-serine (10-160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5-40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5-10 μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.

Topics: Amino Acids; Animals; Autism Spectrum Disorder; Cognition; Cognition Disorders; Cycloserine; Dose-Response Relationship, Drug; Freezing Reaction, Cataleptic; Glycine; Glycine Agents; Male; Memory, Short-Term; Motor Activity; Neurotransmitter Uptake Inhibitors; Nootropic Agents; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Sarcosine; Schizophrenia; Scopolamine; Serine; Social Behavior

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.

Topics: Acetates; Amino Acid Transport Systems, Neutral; Animals; Antipsychotic Agents; Glycine; Glycine Plasma Membrane Transport Proteins; Hippocampus; Humans; Kinetics; Models, Molecular; Molecular Conformation; Molecular Structure; Piperazines; Rats; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Structure-Activity Relationship