title: Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia.
abstract: BACKGROUND
  Since the hypofunction of the N-methyl-D-aspartate (NMDA) receptor is known to be involved in the pathophysiology of schizophrenia, the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophrenia.
  
  
  OBJECTIVE
  We investigated the efficacy of a glycine transporter 1 (GlyT1) inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms, both of which are poorly managed by current antipsychotics.
  
  
  RESULTS
  A newly synthesized GlyT1 inhibitor, 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (TASP0315003) significantly improved cognitive deficit induced by MK-801 in the object recognition test in rats. Likewise, TASP0315003 significantly improved MK-801 impaired cognition in the social recognition test in rats and also enhanced social memory in treatment-naïve rats. In addition, repeated phencyclidine (PCP) treatment reduced the social interaction of paired mice, which may reflect negative symptoms such as social withdrawal, and both acute and sub-chronic treatment with TASP0315003 reversed the reduction in social interaction induced by PCP. Moreover, TASP0315003 additionally exhibited an antidepressant effect in the forced swimming test in rats. In contrast, TASP0315003 did not affect spontaneous locomotor activity or rotarod performance and did not induce catalepsy, indicating that TASP0315003 does not cause sedation or motor dysfunction, which is sometimes observed with the use of current antipsychotics.
  
  
  CONCLUSIONS
  These results suggest that GlyT1 inhibitors including TASP0315003 may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects.
authors: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama, 331-9530, Japan, s-chaki@so.taisho.co.jp.
authors: Shigeyuki
authors: S
authors: Chaki
authors: Toshiharu
authors: T
authors: Shimazaki
authors: Jun-Ichi
authors: J
authors: Karasawa
authors: Takeshi
authors: T
authors: Aoki
authors: Ayaka
authors: A
authors: Kaku
authors: Michihiko
authors: M
authors: Iijima
authors: Daiji
authors: D
authors: Kambe
authors: Shuji
authors: S
authors: Yamamoto
authors: Yasunori
authors: Y
authors: Kawakita
authors: Tsuyoshi
authors: T
authors: Shibata
authors: Kumi
authors: K
authors: Abe
authors: Taketoshi
authors: T
authors: Okubo
authors: Yoshinori
authors: Y
authors: Sekiguchi
authors: Shigeru
authors: S
authors: Okuyama
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D010622:Phencyclidine; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012919:Social Behavior
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine; D005998:Glycine