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

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

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Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA.


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.

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