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 σ1 and σ2 ligands, we synthesized and tested on σ subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modifications on the aralkyl moiety was studied in a systematic way. The affinity of the compounds here described varied to a great extent, with a σ2/σ1 selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to bind to σ1 receptors in a different way than piperidines, we synthesized and tested a series of piperazine compounds; the comparison of their affinity with that of the corresponding piperidines strongly supports the possibility of a different binding mode. While the compounds here described are on the whole selective for σ vs serotonin 5-HT1A and dopamine D2 receptors, 9aa, 9ba and 9ab possess a remarkable affinity for both σ and 5-HT1A receptors, with Ki in the nanomolar range, and are selective with respect to D2 receptors. They displayed also a partial agonist profile in a human 5-HT1A [35S]GTPγS binding assay, suggesting their potential use as atypical antipsychotic agents.