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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

Christina Meyer, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Valentina Dal Col, Erik Laurini, Kenichiro Itami, Sabrina Pricl, and Bernhard Wünsch

J. Med. Chem. 2012, ASAP. DOI: 10.1021/jm300894h


To explore the hydrophobic binding region of the σ1 receptor protein, regioisomeric spirocyclic thiophenes 911 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/Ag2CO3 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.

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