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1型甘氨酸转运体抑制剂N-[3-(4'-氟苯基)-3-(4'-苯氧基苯基)丙基]肌氨酸在体内增强NMDA受体介导的反应,并在啮齿动物行为中产生抗精神病特征。

The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior.

作者信息

Kinney Gene G, Sur Cyrille, Burno Maryann, Mallorga Pierre J, Williams Jacinta B, Figueroa David J, Wittmann Marion, Lemaire Wei, Conn P Jeffrey

机构信息

Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

出版信息

J Neurosci. 2003 Aug 20;23(20):7586-91. doi: 10.1523/JNEUROSCI.23-20-07586.2003.

Abstract

Glycine acts as a necessary coagonist for glutamate at the NMDA receptor (NMDAR) complex by binding to the strychnine-insensitive glycine-B binding site on the NR1 subunit. The fact that glycine is normally found in the brain and spinal cord at concentrations that exceed those required to saturate this site has led to the speculation that glycine normally saturates NMDAR-containing synapses in vivo. However, additional lines of evidence suggest that synaptic glycine may be efficiently regulated in synaptic areas by the glycine transporter type 1 (GlyT1). The recent description of a potent and selective GlyT1 inhibitor (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine [NFPS]) provides a tool for evaluation of the hypothesis that inhibition of GlyT1 may increase synaptic glycine and thereby potentiate NMDAR function in vivo. In the present study, we found that (+)-NFPS demonstrated >10-fold greater activity in an in vitro functional glycine reuptake assay relative to the racemic compound. In vivo, (+/-)-NFPS significantly enhanced long-term potentiation in the hippocampal dentate gyrus induced by high-frequency electrical stimulation of the afferent perforant pathway. Furthermore, (+)-NFPS induced a pattern of c-Fos immunoreactivity comparable with the atypical antipsychotic clozapine and enhanced prepulse inhibition of the acoustic startle response in DBA/2J mice, a strain with low basal levels of prepulse inhibition. Collectively, these data suggest that selective inhibition of GlyT1 can enhance NMDAR-sensitive activity in vivo and also support the idea that GlyT1 may represent a novel target for developing therapeutics to treat disorders associated with NMDAR hypofunction.

摘要

甘氨酸通过与NR1亚基上对士的宁不敏感的甘氨酸B结合位点结合,在N-甲基-D-天冬氨酸受体(NMDAR)复合物中作为谷氨酸的必要协同激动剂。甘氨酸在大脑和脊髓中的浓度通常超过饱和该位点所需的浓度,这一事实引发了这样的推测:甘氨酸在体内通常使含有NMDAR的突触饱和。然而,更多证据表明,突触甘氨酸可能在突触区域被1型甘氨酸转运体(GlyT1)有效调节。最近对一种强效且选择性的GlyT1抑制剂(N-[3-(4'-氟苯基)-3-(4'-苯基苯氧基)丙基]肌氨酸[NFPS])的描述,为评估抑制GlyT1可能增加突触甘氨酸从而增强体内NMDAR功能这一假说提供了一种工具。在本研究中,我们发现(+)-NFPS在体外功能性甘氨酸再摄取试验中的活性比消旋化合物高10倍以上。在体内,(±)-NFPS显著增强了传入穿通通路高频电刺激诱导的海马齿状回中的长时程增强。此外,(+)-NFPS诱导的c-Fos免疫反应模式与非典型抗精神病药物氯氮平相当,并增强了DBA/2J小鼠(一种预脉冲抑制基础水平较低的品系)对听觉惊吓反应的预脉冲抑制。总体而言,这些数据表明,选择性抑制GlyT1可增强体内对NMDAR敏感的活性,也支持了GlyT1可能代表开发治疗与NMDAR功能低下相关疾病的疗法的新靶点这一观点。

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本文引用的文献

2
Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13675-80. doi: 10.1073/pnas.182412499. Epub 2002 Oct 3.
5
ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter.
Mol Pharmacol. 2001 Dec;60(6):1414-20. doi: 10.1124/mol.60.6.1414.
6
The DBA/2J strain and prepulse inhibition of startle: a model system to test antipsychotics?
Psychopharmacology (Berl). 2001 Jul;156(2-3):284-90. doi: 10.1007/s002130100828.
8
Intracellular modulation of NMDA receptor function by antipsychotic drugs.
J Neurosci. 2000 Jun 1;20(11):4011-20. doi: 10.1523/JNEUROSCI.20-11-04011.2000.
9
NMDA receptor hypofunction model of schizophrenia.
J Psychiatr Res. 1999 Nov-Dec;33(6):523-33. doi: 10.1016/s0022-3956(99)00029-1.
10
A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors.
Biol Psychiatry. 1999 Mar 15;45(6):668-79. doi: 10.1016/s0006-3223(98)00237-6.

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