title: Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression.
abstract: Compounds possessing more than one functional activity incorporated into the same molecule may have advantages in treating complex disease states. Balanced serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., (R)- and (S)-norduloxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) showed moderately potent serotonin reuptake inhibition (IC(50) values of 442 and 404 nM, respectively) but low reuptake inhibition of norepinephrine (IC(50) values of 2097 and 2190 nM, respectively) in vitro. The dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) also inhibited PDE4D2 (i.e., K(i) values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression.
authors.affiliation: Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA. Jcashman@HBRI.org
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
authors.forename: Senait
authors.initials: S
authors.lastname: Ghirmai
mesh_terms: D003432:Cross-Linking Reagents; D003863:Depression / Q000188:drug therapy*; D003866:Depressive Disorder / Q000188:drug therapy; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D009638:Norepinephrine / Q000819:agonists; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D003432:Cross-Linking Reagents; D009638:Norepinephrine; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors