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, Bernhard Wünsch

*この研究の対応する著者

研究成果: Article査読

45 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)8047-8065
ページ数19
ジャーナルJournal of Medicinal Chemistry
55
18
DOI
出版ステータスPublished - 2012 9 27
外部発表はい

ASJC Scopus subject areas

  • 分子医療
  • 創薬

フィンガープリント

「Pd-catalyzed direct C-H bond functionalization of spirocyclic σ<sub>1</sub> ligands: Generation of a pharmacophore model and analysis of the reverse binding mode by Docking into a 3D homology model of the σ<sub>1</sub> receptor」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

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