Synthesis and in vitro binding studies of piperazine-alkyl-naphthamides: Impact of homology and sulphonamide/carboxamide bioisosteric replacement on the affinity for 5-HT1A, α2A, D4.2, D3 and D2L receptors

A series of carboxamide and sulphonamide alkyl(ethyl to hexyl)piperazine analogues were prepared and tested for their affinity to bind to a range of receptors potentially involved in psychiatric disorders. These chemical modifications led us to explore the impact of homology and bioisosteric replacement of the amide group. All of these compounds possessed a high affinity for 5-HT1A receptors, irrespective of the size of the linker, the carboxamide derivative with a pentyl linker had the highest affinity for α2A receptor sites and also a high affinity for 5-HT1A and D3 receptors. The sulphonamide analogue with a hexyl linker possessed a high affinity for 5-HT1A, D4.2 and D3 receptors.

Graphical abstractA series of piperazine-alkyl-naphthamides (R = CO or SO2; n = 1–5) was prepared and tested for their affinity for 5-HT1A, α2A, D4.2, D3 and D2L receptors. Homology and sulphonamide/carboxamide isosteric replacement differentially affect the binding affinity for these receptors.Figure optionsDownload full-size imageDownload as PowerPoint slide