Dual inhibitors of phosphodiesterase-4 and serotonin reuptake.
Article Details
- CitationCopy to clipboard
Cashman JR, Voelker T, Zhang HT, O'Donnell JM
Dual inhibitors of phosphodiesterase-4 and serotonin reuptake.
J Med Chem. 2009 Mar 26;52(6):1530-9. doi: 10.1021/jm8010993.
- PubMed ID
- 19256502 [ View in PubMed]
- Abstract
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)-pen tyl]-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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cocaine Sodium-dependent dopamine transporter Ki (nM) 371 7.4 22 Details Cocaine Sodium-dependent dopamine transporter EC 50 (nM) 303 7.4 22 Details Cocaine Sodium-dependent noradrenaline transporter Ki (nM) 1115 7.4 22 Details Cocaine Sodium-dependent noradrenaline transporter EC 50 (nM) 835 7.4 22 Details Cocaine Sodium-dependent serotonin transporter Ki (nM) 276 7.4 22 Details Cocaine Sodium-dependent serotonin transporter EC 50 (nM) 416 7.4 22 Details Fluoxetine Sodium-dependent serotonin transporter Ki (nM) 1.1 7.4 22 Details Fluoxetine Sodium-dependent serotonin transporter EC 50 (nM) 7.3 7.4 22 Details