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

Bioorg Med Chem. 2009 Jan 1;17(1):337-43. doi: 10.1016/j.bmc.2008.10.065. Epub 2008 Nov 5.


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 (IC(50) values of 173 and 42 nM, respectively) in vitro. The dual PDE4 inhibitor/SSRIs (R)-8 and (S)-8 also inhibited PDE4D2 (i.e., K(i) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / chemical synthesis*
  • Cross-Linking Reagents
  • Drug Delivery Systems
  • Drug Synergism
  • Humans
  • Inhibitory Concentration 50
  • Phosphodiesterase 4 Inhibitors
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / pharmacology
  • Selective Serotonin Reuptake Inhibitors / chemistry*
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Stereoisomerism


  • Antidepressive Agents
  • Cross-Linking Reagents
  • Phosphodiesterase 4 Inhibitors
  • Phosphodiesterase Inhibitors
  • Serotonin Uptake Inhibitors