Dual inhibitors of phosphodiesterase-4 and serotonin reuptake.
A new class of multitarget compounds was synthesized by linking a novel selective serotonin reuptake inhibitor (SSRI) to a PDE4 inhibitor. The new dual PDE4 inhibitor/SSRI showed antidepressant-like activity in the forced swim test in mice The SSRIs 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine (14) and 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamine (15) were both individually linked to the PDE4 inhibitor 4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (19), via a five-carbon chain. The dual PDE4 inhibitor/SSRI 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine)-pentyl]-4,5,8,8a-tetrahydro-2H-phthalazin-1-one (21) showed potent and selective serotonin reuptake inhibition (IC(50) value of 127 nM). The dual PDE4 inhibitor/SSRI 21 also inhibited PDE4D3 with a K(i) value of 2.0 nM. The dual PDE4 inhibitor/SSRI was significantly more effective than the individual SSRI alone or fluoxetine in the forced swim test at standard doses. On a molar basis, the antidepressant-like effect of the dual PDE4 inhibitor/SSRI 21 showed a 129-fold increase in in vivo efficacy compared to fluoxetine.
Cashman
John R
JR
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121, USA. jcashman@hbri.org
Voelker
Troy
T
Zhang
Han-Ting
HT
O'Donnell
James M
JM
D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors