Dual inhibitors of phosphodiesterase-4 and serotonin reuptake.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
CocaineSodium-dependent dopamine transporterKi (nM)3717.422Details
CocaineSodium-dependent dopamine transporterEC 50 (nM)3037.422Details
CocaineSodium-dependent noradrenaline transporterKi (nM)11157.422Details
CocaineSodium-dependent noradrenaline transporterEC 50 (nM)8357.422Details
CocaineSodium-dependent serotonin transporterKi (nM)2767.422Details
CocaineSodium-dependent serotonin transporterEC 50 (nM)4167.422Details
FluoxetineSodium-dependent serotonin transporterKi (nM)1.17.422Details
FluoxetineSodium-dependent serotonin transporterEC 50 (nM)7.37.422Details