Exploitation of an additional hydrophobic pocket of σ 1 receptors

Late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization

Christina Meyer, Benedikt Neue, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Ernst Ulrich Würthwein, Kenichiro Itami, Bernhard Wünsch

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The hypothesis that the σ 1 receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ 1 receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the σ 1 receptor protein. The catalyst system PdCl 2/2,2′-bipyridyl/Ag 2CO 3 is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ 1 affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ 1 affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ 1 receptor ligands (3a: K i = 4.5 nM; 4a: K i = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ 1 receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ 1 affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ 1 affinity. However, decrease of σ 1 affinity by extension of the π-system to a biphenylyl substituent (4j: K i = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the σ 1 receptor.

Original languageEnglish
Pages (from-to)8016-8029
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume9
Issue number23
DOIs
Publication statusPublished - 2011 Dec 7
Externally publishedYes

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Thiophenes
exploitation
thiophenes
affinity
Ligands
ligands
Derivatives
2,2'-Dipyridyl
Discrete Fourier transforms
proteins
Proteins
Substitution reactions
Catalysts
substitutes
catalysts
preparation
synthesis

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry

Cite this

Exploitation of an additional hydrophobic pocket of σ 1 receptors : Late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization. / Meyer, Christina; Neue, Benedikt; Schepmann, Dirk; Yanagisawa, Shuichi; Yamaguchi, Junichiro; Würthwein, Ernst Ulrich; Itami, Kenichiro; Wünsch, Bernhard.

In: Organic and Biomolecular Chemistry, Vol. 9, No. 23, 07.12.2011, p. 8016-8029.

Research output: Contribution to journalArticle

Meyer, Christina ; Neue, Benedikt ; Schepmann, Dirk ; Yanagisawa, Shuichi ; Yamaguchi, Junichiro ; Würthwein, Ernst Ulrich ; Itami, Kenichiro ; Wünsch, Bernhard. / Exploitation of an additional hydrophobic pocket of σ 1 receptors : Late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization. In: Organic and Biomolecular Chemistry. 2011 ; Vol. 9, No. 23. pp. 8016-8029.
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