Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia

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• 作者：Shigeyuki Chaki ; Toshiharu Shimazaki ; Jun-ichi Karasawa ; Takeshi Aoki…
• 关键词：Glycine transporter 1 inhibitor ; Schizophrenia ; Negative symptoms ; Cognitive dysfunction ; TASP0315003
• 刊名：Psychopharmacology
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：232
• 期：15
• 页码：2849-2861
• 全文大小：547 KB
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• 作者单位：Shigeyuki Chaki (1)
  Toshiharu Shimazaki (1)
  Jun-ichi Karasawa (1)
  Takeshi Aoki (1)
  Ayaka Kaku (1)
  Michihiko Iijima (1)
  Daiji Kambe (1)
  Shuji Yamamoto (2)
  Yasunori Kawakita (3)
  Tsuyoshi Shibata (2)
  Kumi Abe (2)
  Taketoshi Okubo (2)
  Yoshinori Sekiguchi (2)
  Shigeru Okuyama (4)
  
  1. Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama, 331-9530, Japan
  2. Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama, 331-9530, Japan
  3. Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama, 331-9530, Japan
  4. Research Headquarters, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama, 331-9530, Japan
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Psychiatry
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-2072

文摘

Rationale 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. Objectives 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-na?ve 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.