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摘要
精神分裂症是一种复杂的神经精神障碍,其治疗方法选择有限,具有高度神经衰弱的症状,对个人,社会以及受其折磨个人的职业造成了不良后果。我们目前对于精神分裂症的理解为,多巴胺和谷氨酸系统在其发病机制中起着重要的作用 。尿喹啉酸,一种内源性谷氨酸拮抗剂,发现该成分在精神分裂症患者前额叶皮层和脑脊液的浓度有升高,从而影响神经递质的释放。它的作用类似于以前研究的拟精神病药物,如强调分子基础与精神分裂症的病理生理学联系的苯环己哌啶。犬尿氨酸是色氨酸在犬尿氨酸氨基转移酶(KAT)的催化下,发生转氨基作用生成的中间代谢产物。文献报道了4个KAT的同系物,都是5''-磷酸吡哆醛依赖酶。在结构和生物化学方面,对这4个亚型都进行了分析,其中研究最广泛的是KAT-I和KAT-II。基于结构的药物设计我们发现了这两种酶,它们能使犬尿喹啉酸回复正常化水平。最有效的KAT-I型抑制剂和KAT-II型抑制剂分别包括苯腙己酸衍生物和吡唑系列化合物。动物研究表明,KAT抑制剂能有效减少犬尿喹啉酸的生成,伴随改变神经递质的释放和改善认知效应。本综述将探讨不同的KAT亚型的特点,并着重讨论重要KAT抑制剂的发展前景。KAT抑制剂在治疗精神分裂症中具有很大的潜力,也是治疗精神分裂症的一种新方法。
关键词: BFF-122
Current Medicinal Chemistry
Title:Kynurenine Aminotransferases and the Prospects of Inhibitors for the Treatment of Schizophrenia
Volume: 22 Issue: 24
Author(s): Gayan S. Jayawickrama, Richard R. Sadig, Guanchen Sun, Alireza Nematollahi, Naveed A. Nadvi, Jane R. Hanrahan, Mark D. Gorrell and W. Bret Church
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关键词: BFF-122
摘要: Schizophrenia is a complex neuropsychiatric disorder with limited treatment options and highly debilitating symptoms, leading to poor personal, social, and occupational outcomes for an afflicted individual. Our current understanding of schizophrenia suggests that dopaminergic and glutamatergic systems have a significant role in the pathogenesis of the disease. Kynurenic acid, an endogenous glutamate antagonist, is found in elevated concentrations in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia, and this affects neurotransmitter release in a similar manner to previously observed psychotomimetic agents, such as phencyclidine, underlining the molecular basis to its link in schizophrenia pathophysiology. Kynurenic acid is a breakdown product of tryptophan degradation, through a transamination process mediated by kynurenine aminotransferase (KAT) enzymes. There are four KAT homologues reported, all of which are pyridoxal 5’- phosphate-dependent enzymes. All four KAT isoforms have been analysed structurally and biochemically, however the most extensive research is on KAT-I and KAT-II. These two enzymes have been targeted in structure-based drug design as a means of normalising raised kynurenic acid levels. The most potent KAT-I inhibitors and KAT-II inhibitors include phenylhydrazone hexanoic acid derivatives and a pyrazole series of compounds, respectively. KAT inhibitors have been shown to be effective in reducing kynurenic acid production, with accompanying changes in neurotransmitter release and pro-cognitive effects seen in animal studies. This review will discuss the characteristics pertaining to the different KAT isoforms, and will highlight the development of significant KAT inhibitors. KAT inhibitors have great potential for therapeutic application and represent a novel way in treating schizophrenia.
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Gayan S. Jayawickrama , Richard R. Sadig , Guanchen Sun , Alireza Nematollahi , Naveed A. Nadvi , Jane R. Hanrahan , Mark D. Gorrell and W. Bret Church , Kynurenine Aminotransferases and the Prospects of Inhibitors for the Treatment of Schizophrenia, Current Medicinal Chemistry 2015; 22 (24) . https://dx.doi.org/10.2174/0929867322666150608094054
DOI https://dx.doi.org/10.2174/0929867322666150608094054 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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