阿尔茨海默病β淀粉样蛋白钙通道的小分子阻滞剂能有效保护神经元免受β淀粉样蛋白的细胞毒性作用。
Small molecule blockers of the Alzheimer Abeta calcium channel potently protect neurons from Abeta cytotoxicity.
作者信息
Diaz Juan Carlos, Simakova Olga, Jacobson Kenneth A, Arispe Nelson, Pollard Harvey B
机构信息
Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA.
出版信息
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3348-53. doi: 10.1073/pnas.0813355106. Epub 2009 Feb 9.
Abstract
Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (Abeta). We have hypothesized that the intrinsic Abeta calcium channel activity of the oligomeric Abeta polymer may be responsible for the neurotoxic properties of Abeta, and that Abeta channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the Abeta channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the Abeta channel and protect neurons from Abeta toxicity. Both block the Abeta channel with similar potency (approximately 500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.
摘要
阿尔茨海默病（AD）是一种常见的慢性神经退行性疾病，被认为是由β淀粉样肽（Aβ）的神经毒性作用引起的。我们推测，寡聚Aβ聚合物的内在Aβ钙通道活性可能是Aβ神经毒性特性的原因，并且Aβ通道阻滞剂可能是AD治疗的候选药物。基于Aβ通道的模型结构进行合理的搜索范式，我们确定了两种感兴趣的化合物：MRS2481和一种对映体MRS2485。这些是两亲性吡啶鎓盐，它们都能有效阻断Aβ通道并保护神经元免受Aβ毒性。两者以相似的效力（约500 nM）和功效（100%）阻断Aβ通道。然而，我们发现MRS2481的抑制作用很容易逆转，而MRS2485的抑制作用几乎是不可逆的。我们认为这两种化合物都值得作为阿尔茨海默病药物发现的候选药物加以考虑。
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