Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ1 Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one De

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• 作者：Daniele Zampieri ; Maria Grazia Mamolo ; Erik Laurini ; Chiara Florio ; Caterina Zanette ; Maurizio Fermeglia ; Paola Posocco ; Maria Silvia Paneni ; Sabrina Pricl ; Luciano Vio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 10, 2009
• 年：2009
• 卷：52
• 期：17
• 页码：5380-5393
• 全文大小：1059K
• 年卷期：v.52,no.17(September 10, 2009)
• ISSN：1520-4804

文摘

Novel benzo[d]oxazol-2(3H)-one derivatives were designed and synthesized, and their affinities against σ receptors were evaluated. On the basis of 31 compounds, a three-dimensional pharmacophore model for the σ₁ receptor binding site was developed using the Catalyst 4.9 software package. The best 3D pharmacophore hypothesis, consisting of one positive ionizable, one hydrogen bond acceptor, two hydrophobic aromatic, and one hydrophobic features provided a 3D-QSAR model with a correlation coefficient of 0.89. The best hypothesis was also validated by three independent methods, i.e., the Fisher randomization test included in the CatScramble functionality of Catalyst, the leave-one-out test, and activity prediction of an additional test set. The achieved results will allow researchers to use this 3D pharmacophore model for the design and synthesis of a second generation of high affinity σ₁ ligands, as well as to discover other lead compounds for this class of receptors.