Pd-catalyzed direct C-H bond functionalization of spirocyclic σ₁ ligands: Generation of a pharmacophore model and analysis of the reverse binding mode by Docking into a 3D homology model of the σ₁ receptor

To explore the hydrophobic binding region of the σ₁ receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective α- and β-arylation using the catalyst systems PdCl₂/bipy/Ag₂CO₃ and PdCl₂/P[OCH(CF₃)₂]₃/Ag ₂CO₃ allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing σ₁ 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 σ₁ affinity. The main features of the pharmacophore model developed for this class of σ₁ 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 σ₁ 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.