Structure–activity relationships in 1,4-benzodioxan-related compounds. 10. Novel α₁-adrenoreceptor antagonists related to openphendioxan: Synthesis, biological evaluation, and α_1d computational study

详细信息    查看全文

• 作者：Antonio Carrieri ; Aless ; ro Piergentili ; Fabio Del Bello ; Mario Giannella ; Maria Pigini ; Amedeo Leonardi ; Francesca Fanelli ; Wilma Quaglia
• 关键词：GPCRs ; α ; ₁-Adrenoreceptor antagonists ; Openphendioxan analogues ; QSAR ; Comparative modeling ; Docking
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：1 October 2010
• 年：2010
• 卷：18
• 期：19
• 页码：7065-7077
• 全文大小：1207 K

文摘

A series of novel openphendioxan analogues were synthesized and tested at α₁-adrenoreceptor (AR) subtypes by binding and functional assays. The α_1d-AR binding profile was also examined by means of 2D, 3D-QSAR together with docking studies. Multiple regression analysis suggested the relevance of adequate number of heteroatoms in the whole molecule and of passive membrane diffusion to enhance α_1d-AR affinity. Docking simulations against a computational structural model of the biological target further proved this evidence and furnished support for chemiometric analysis, where polar, electrostatic, hydrophobic and shape effects of the ortho substituents in the phenoxy terminal, most likely governing ligand binding, helped the depiction of pharmacophore hypothesis for the examined ligands data set.