Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression

John R. Cashman, Troy Voelker, Robert Johnson, Aaron Janowsky

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Multi-target compounds where more than one functional activity is incorporated into the same molecule may have advantages in treating disease states. Selective serotonin re-uptake inhibitors (SSRIs)a (i.e., (R)- and (S)-norfluoxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual PDE4 inhibitor/SSRIs (i.e., (R)-8 and (S)-8) showed moderately potent but highly selective serotonin re-uptake inhibition (IC50 values of 173 and 42 nM, respectively) in vitro. The dual PDE4 inhibitor/SSRIs (R)-8 and (S)-8 also inhibited PDE4D2 (i.e., Ki values of 106 and 253 nM, respectively). Due to the synergistic functional activity, PDE4 inhibitor/SSRIs may be effective in treating diseases such as depression.

Original languageEnglish (US)
Pages (from-to)337-343
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Depression
  • Dual selective serotonin re-uptake inhibitor/PDE4 inhibitor
  • Fluoxetine
  • Transporters

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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