Synthesis and Structure-Activity Relationships of 1-Aralkyl-4-Benzylpiperidine and 1-Aralkyl-4-Benzylpiperazine Derivatives as Potent sigma Ligands.

In the attempt to define more accurately structure-affinity relationships for \uf31 and \uf32 ligands,we synthesized and tested on \uf3 subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine,in which the effect of modifications on the aralkyl moiety was studied in a systematicway. The affinity of the compounds here described varied to a great extent, with a \uf32/\uf31selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative tobind to \uf31 receptors in a different way than piperidines, we synthesized and tested a series ofpiperazine compounds; the comparison of their affinity with that of the correspondingpiperidines strongly supports the possibility of a different binding mode. While the compoundshere described are on the whole selective for \uf3 vs serotonin 5-HT1A and dopamine D2 receptors,9aa, 9ba and 9ab possess a remarkable affinity for both \uf3 and 5-HT1A receptors, with Ki inthe nanomolar range, and are selective with respect to D2 receptors. They displayed also apartial agonist profile in a human 5-HT1A [35S]GTP\ue7S binding assay, suggesting their potentialuse as atypical antipsychotic agents