Dual Inhibitors of Phosphodiesterase-4 and Serotonin Reuptake

Abstract

A new class of multi-target compounds was synthesized by linking a novel selective serotonin reuptake inhibitor (SSRI)a to a PDE4 inhibitor. The new dual PDE4 inhibitor/SSRI showed antidepressant-like activity in the forced swim test in mice The SSRIs 14, 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine and 15, 2-{5-[3-(5-fluoro-2-methoxyphenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamine were both individually linked to the PDE4 inhibitor 19, (4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one) via a five carbon chain. The dual PDE4 inhibitor/SSRI 21, 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine)-pentyl]-4,5,8,8a-tetrahydro-2H-phthalazin-1-one 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.

Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression

“…Loss of affinity and reuptake inhibition of the hNET by 15 suggests this transporter is considerably more sensitive to steric bulk than the hSERT in agreement with previous studies. 17,20 However, the stereoselectivity for hSERT binding (i.e., R > S) observed for norduloxetine was considerably attenuated for the dual SNRI/PDE4 inhibitor 15. Reuptake inhibition of the hSERT by 15 was not stereoselective suggesting that hSERT binding and reuptake inhibition are distinct.…”

Exploring Polypharmacology Using a ROCS-Based Target Fishing Approach

“…A literature analysis shows that fluoxetine was known to have a weak binding affinity for the norepinephrine transporter (K i = 1560 nM) and dopamine transporter (K i = 6670 nM). 48 Fluoxetine was also known to have histamine H1 receptor Figure 9. The drug−target matrix generated for a test molecule (shown as query 4).…”

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

“…Under this hypothesis several SSRIs, such as (R)-and (S)-norfluoxetine as well as some furylalkylamines, were linked to the (±)-cis-tetrahydrophthalazinone scaffold, key pharmacophore for selective PDE4 inhibition [88,89], via a five carbon bridge in order to develop dual SSRI/PDE4 inhibitors [26,132]. The described compounds ((R)-113, (S)-113, 114 and 115, Figure 19) showed moderately potent but highly selective 5-HT re-uptake inhibition and significant inhibition of some recombinant PDE4 isoforms in vitro.…”

“…The described compounds ((R)-113, (S)-113, 114 and 115, Figure 19) showed moderately potent but highly selective 5-HT re-uptake inhibition and significant inhibition of some recombinant PDE4 isoforms in vitro. In addition, the in vivo studies for acute and sub-chronic antidepressant-like effects using forced-swim test in mice indicated that compound 114 was more effective than fluoxetine, used as standard drug [132].…”