Structure-activity relationships in 1,4-benzodioxan-related compounds. 10. Novel a sub(1)-adrenoreceptor antagonists related to openphendioxan: Synthesis, biological evaluation, and a sub(1d) computational study

A series of novel openphendioxan analogues were synthesized and tested at a sub(1)-adrenoreceptor (AR) subtypes by binding and functional assays. The a sub(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 a sub(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.