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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >N-acetyl serotonin derivatives as potent neuroprotectants for retinas
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N-acetyl serotonin derivatives as potent neuroprotectants for retinas

机译：N-乙酰基5-羟色胺衍生物作为视网膜的有效神经保护剂

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摘要

N-acetylserotonin (NAS) is synthesized from serotonin by arylalkyl-amine N-acetyltransferase (AANAT), which is predominantly expressed in the pineal gland and retina. NAS activates TrkB in a circadian manner and exhibits antidepressant effects in a TrkB-de-pendent manner. It also enhances neurogenesis in hippocampus in sleep-deprived mice. Here we report the identification of NAS derivatives that possess much more robust neurotrophic effects with improved pharmacokinetic profiles. The compound A?-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD), which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases.
机译：N-乙酰5-羟色胺（NAS）是由5-羟色胺通过芳基烷基胺N-乙酰基转移酶（AANAT）合成的，主要在松果体和视网膜中表达。 NAS以昼夜节律的方式激活TrkB，并以TrkB依赖性的方式表现出抗抑郁作用。它还可增强睡眠不足小鼠海马神经元的生成。在这里，我们报告鉴定具有更强的神经营养作用和改善的药代动力学特征的NAS衍生物。化合物Aβ-[2-（5-羟基-1H-吲哚-3-基）乙基] -2-氧哌啶-3-甲酰胺（HIOC）选择性地活化TrkB受体，其效力高于NAS。它有效地保护了视网膜免于光诱导的视网膜变性（LIRD），这与视网膜中明显的TrkB激活紧密相关。药代动力学研究表明该化合物在血清和肝微粒体中稳定。它可以通过血脑屏障和血视网膜屏障。因此，HIOC是用于进一步治疗视网膜变性疾病的药物开发的良好先导化合物。

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  • 作者

    Jianying Shen; Kanika Ghai; Pradoldej Sompol; Xia Liu; Xuebing Cao; P. Michael luvone; Keqiang Ye;

  • 作者单位

    Departments of Pathology and Laboratory Medicine, Emory University School of Medicine Atlanta, GA 30322;

    Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;

    Departments of Pathology and Laboratory Medicine, Emory University School of Medicine Atlanta, GA 30322;

    Departments of Pathology and Laboratory Medicine, Emory University School of Medicine Atlanta, GA 30322;

    Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;

    Departments of Ophthalmology and Pharmacology, Emory University School of Medicine Atlanta, GA 30322;

    Departments of Pathology and Laboratory Medicine, Emory University School of Medicine Atlanta, GA 30322;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    circadian rhythm; melatonin; small molecule; neurotrophins;

    机译：昼夜节律褪黑激素小分子神经营养蛋白;

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