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 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(2)CO(3) and PdCl(2)/P[OCH(CF(3))(2)](3)/Ag(2)CO(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.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Christina
C
Meyer
Dirk
D
Schepmann
Shuichi
S
Yanagisawa
Junichiro
J
Yamaguchi
Valentina
V
Dal Col
Erik
E
Laurini
Kenichiro
K
Itami
Sabrina
S
Pricl
Bernhard
B
Wünsch
D002384:Catalysis; D015195:Drug Design; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D010165:Palladium / Q000737:chemistry*; D011485:Protein Binding; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
D008024:Ligands; D010165:Palladium; D017480:Receptors, sigma; D013141:Spiro Compounds; D000097605:Sigma-1 Receptor