Santana Lourdes, González-Díaz Humberto, Quezada Elías, Uriarte Eugenio, Yáñez Matilde, Viña Dolores, Orallo Francisco
Department of Organic Chemistry, Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela 15782, Spain.
J Med Chem. 2008 Nov 13;51(21):6740-51. doi: 10.1021/jm800656v. Epub 2008 Oct 4.
The work provides a new model for the prediction of the MAO-A and -B inhibitor activity by the use of combined complex networks and QSAR methodologies. On the basis of the obtained model, we prepared and assayed 33 coumarin derivatives, and the theoretical prediction was compared with the experimental activity data. The model correctly predicted 27 compounds, and most of the active derivatives showed IC 50 values in the muM-nM range against both the MAO-A and MAO-B isoforms. Compound 14 shows the same MAO-A inhibitory activity (IC 50 = 7.2 nM), as clorgyline used as a reference inhibitor and has the highest MAO-A specificity (1000-fold higher compared to MAO-B). On the other hand, compounds 24 (IC 50 = 1.2 nM) and 28 (IC 50 = 1.5 nM) show higher activity than selegiline (IC 50 = 19.6 nM) and high MAO-B selectivity with 100-fold and 1600-fold inhibition levels, with respect to the MAO-A isoform.
该研究通过联合使用复杂网络和定量构效关系（QSAR）方法，为预测单胺氧化酶A（MAO-A）和单胺氧化酶B（MAO-B）抑制剂活性提供了一种新模型。基于所获得的模型，我们制备并测定了33种香豆素衍生物，并将理论预测结果与实验活性数据进行了比较。该模型正确预测了27种化合物，大多数活性衍生物对MAO-A和MAO-B亚型的半数抑制浓度（IC50）值在微摩尔至纳摩尔范围内。化合物14表现出与用作参考抑制剂的氯吉兰相同的MAO-A抑制活性（IC50 = 7.2 nM），并且具有最高的MAO-A特异性（与MAO-B相比高1000倍）。另一方面，化合物24（IC50 = 1.2 nM）和化合物28（IC50 = 1.5 nM）表现出比司来吉兰（IC50 = 19.6 nM）更高的活性，并且相对于MAO-A亚型，对MAO-B具有100倍和1600倍的抑制水平，具有高MAO-B选择性。
