Cell-Permeable and Plasma-Stable Peptidomimetic Inhibitors of the Postsynaptic Density-95/N-Methyl-d-Aspartate Receptor Interaction

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• 作者：Anders Bach ; Jonas N. N. Eildal ; Nicolai Stuhr-Hansen ; Rasmus Deeskamp ; Marie Gottschalk ; S酶ren W. Pedersen ; Anders S. Kristensen ; Kristian Str酶mgaard
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1333-1346
• 全文大小：1180K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

The protein鈭抪rotein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors of this interaction, and here, this template is exploited for the development of blood plasma-stable and cell-permeable inhibitors. Initially, we explored both the amino acid sequence of the tetrapeptide and the nature of the N-alkyl groups, which consolidated N-cyclohexylethyl-ETAV (1) as the most potent and selective compound. Next, the amide moieties of N-methylated ETAV were systematically replaced with thioamides, demonstrating that one of three amide bonds could be replaced without compromising the affinity. Subsequent optimization of the N-alkyl groups and evaluation of cell permeability led to identification of N-cyclohexylethyl-ETA_SV (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction.