Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile.
Bioorg Med Chem. 2010 Feb 15;18(4):1388-95. doi: 10.1016/j.bmc.2010.01.029. Epub 2010 Jan 15.
2-Arylthiomorpholine and 2-arylthiomorpholin-5-one derivatives, designed as rigid and/or non-basic phenylethylamine analogues, were evaluated as rat and human monoamine oxidase inhibitors. Molecular docking provided insight into the binding mode of these inhibitors and rationalized their different potencies. Making the phenylethylamine scaffold rigid by fixing the amine chain in an extended six-membered ring conformation increased MAO-B (but not MAO-A) inhibitory activity relative to the more flexible alpha-methylated derivative. The presence of a basic nitrogen atom is not a prerequisite in either MAO-A or MAO-B. The best K(i) values were in the 10(-8)M range, with selectivities towards human MAO-B exceeding 2000-fold.
2-芳基硫代吗啉和 2-芳基硫代吗啉-5-酮衍生物被设计为刚性和/或非碱性苯乙胺类似物，被评估为大鼠和人单胺氧化酶抑制剂。分子对接提供了对这些抑制剂结合模式的深入了解，并使它们的不同效力合理化。通过将胺链固定在扩展的六元环构象中使苯乙胺支架刚性，相对于更灵活的α-甲基化衍生物，增加了 MAO-B（但不是 MAO-A）抑制活性。碱性氮原子的存在不是 MAO-A 或 MAO-B 的必要条件。最佳 K(i) 值在 10(-8)M 范围内，对人 MAO-B 的选择性超过 2000 倍。
