Structure–activity relationships of N-substituted piperazine amine reuptake inhibitors

We report the structure–activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (−)-2 lacked potent inhibitory activity against any of the important cytochromes P450 and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.

Graphical abstractThe synthesis and structure–activity relationships are described for 26 variously N-substituted piperazines as dual serotonin/noradrenaline reuptake inhibitors. Compound (R)(−)-2 was a potent, balanced 5-HT/NA reuptake inhibitor with high selectivity over a wide range of GPCRs and demonstrated only weak inhibitory activity versus cytochromes P450.Figure optionsDownload full-size imageDownload as PowerPoint slide