Pd-catalyzed direct C-H bond functionalization of spirocyclic σ _1 ligands: Generation of a pharmacophore model and analysis of the reverse binding mode by Docking into a 3D homology model of the σ _1 receptor

摘要

To explore the hydrophobic binding region of the σ _1 receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective α- and β-arylation using the catalyst systems PdCl _2/bipy/Ag _2CO _3 and PdCl _2/P[OCH(CF 3_) _2] _3/Ag _2CO _3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing σ _1 affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the σ _1 affinity. The main features of the pharmacophore model developed for this class of σ _1 ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a σ _1 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.