Phenserine
Phenserine
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DOI：
10.1517/13543784.16.7.1087
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发表时间：
2007-07-01
影响因子：
6.1
通讯作者：
Klein, Jochen
中科院分区：
文献类型：
--
作者：
Klein, Jochen
Phenserine 是毒扁豆碱的衍生物，最初被描述为乙酰胆碱酯酶 (ACH) 的抑制剂，并在啮齿动物和狗的各种实验范例中被证明可以改善认知能力。它经过了阿尔茨海默病的临床测试，在最初的二期研究中取得了一定的成功。 Phenserine 的额外作用值得关注：除了抑制 ACH 之外，它还通过减少 APP 翻译来调节神经细胞培养物中 β-淀粉样前体蛋白 (APP) 的量。这种效应可能涉及苯酚酚与 APP 基因 5'-非翻译区中控制 APP 表达的调节元件的相互作用。 Phenserine 明显降低了 APP mRNA 转化为蛋白质的效率，这一过程可能涉及与铁和/或铁响应元件的相互作用。因此，苯酚酚可减少体外和体内 β-淀粉样肽 (Aβ) 的形成。 Phenserine 的独特性还在于其对映体的不同作用：(-)-phenserine 是抑制 ACH 的活性对映体，而 (+)-phenserine（“posiphen”）作为 ACH 抑制剂的活性较弱，且剂量可能更高。两种对映体在下调 APP 表达方面是等效的。 (+)-Posiphen 可能是一种很有前途的药物，无论是单独使用还是与 (-)-phenserine 联合使用，都可以减缓阿尔茨海默病的进展。
Phenserine, a derivative of physostigmine, was first described as an inhibitor of acetylcholinesterase (ACH) and was shown to improve cognition in various experimental paradigms in rodents and dogs. It was clinically tested for Alzheimer's disease, with moderate success in initial Phase II studies. Phenserine deserves attention for an additional quality of action: in addition to inhibiting ACH, it modulates the amount of beta-amyloid precursor protein (APP) in neuronal cell culture by reducing APP translation. This effect probably involves interaction of phenserine with a regulatory element in the 5'-untranslated region of the APP gene that controls APP expression. Phenserine apparently reduces translational efficiency of APP mRNA into protein, a process that may involve an interaction with iron and/or an iron-responsive element. As a consequence, phenserine reduces beta-amyloid peptide (A beta) formation in vitro and in vivo. Phenserine is also unique because of differing actions of its enantiomers: (-)-phenserine is the active enantiomer for inhibition of ACH, whereas (+)-phenserine ('posiphen') has weak activity as an ACH inhibitor and can be dosed much higher. Both enantiomers are equipotent in downregulating APP expression. (+)-Posiphen may be a promising drug, either alone or in combination with (-)-phenserine, to attenuate the progression of Alzheimer's disease.