Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression.
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.
Cashman
John R
JR
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA. jcashman@hbri.org
Voelker
Troy
T
Johnson
Robert
R
Janowsky
Aaron
A
D000928:Antidepressive Agents / Q000138:chemical synthesis*; D003432:Cross-Linking Reagents; D016503:Drug Delivery Systems; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
D000928:Antidepressive Agents; D003432:Cross-Linking Reagents; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors