title: Glycine transport inhibitors in the treatment of schizophrenia.
abstract: Schizophrenia is a severe neuropsychiatric disorder without adequate current treatment. Recent theories of schizophrenia focus on disturbances of glutamatergic neurotransmission particularly at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine type I (GlyT1) transporters, which serve to maintain low subsaturating glycine levels in the vicinity of the NMDA receptor. A proposed approach to treatment of schizophrenia, therefore, is inhibition of GlyT1-mediated transport. Over the past decade, several well tolerated, high affinity GlyT1 inhibitors have been developed and shown to potentiate NMDA receptor-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GlyT1 inhibitor, and with the high affinity compound RG1678. Although definitive trials remain ongoing, encouraging results to date have been reported.
authors.affiliation: Nathan S Kline Institute for Psychiatric Research, Columbia University, Orangeburg, NY 10962, USA. javitt@nki.rfmh.org
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Javitt
mesh_terms: D000818:Animals; D005998:Glycine / Q000502:physiology; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D010879:Piperazines / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy*; D013450:Sulfones / Q000627:therapeutic use
chemical_list: C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D050487:Glycine Plasma Membrane Transport Proteins; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D013450:Sulfones; D005998:Glycine