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

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8047-8065
Number of pages19
JournalJournal of Medicinal Chemistry
Volume55
Issue number18
DOIs
Publication statusPublished - 2012 Sep 27
Externally publishedYes

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Thiophenes
Ligands
Molecular Models
Mechanics
Proteins
palladium chloride

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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

In: Journal of Medicinal Chemistry, Vol. 55, No. 18, 27.09.2012, p. 8047-8065.

Research output: Contribution to journalArticle

Meyer, Christina ; Schepmann, Dirk ; Yanagisawa, Shuichi ; Yamaguchi, Junichiro ; Dal Col, Valentina ; Laurini, Erik ; Itami, Kenichiro ; Pricl, Sabrina ; Wünsch, Bernhard. / 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. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 18. pp. 8047-8065.
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