3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives: high-affinity ligands for the serotonin transporter

The structural requirements for high-affinity binding at the serotonin transporter (SERT) have been investigated through the preparation of some 3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives. The affinity of synthesised piperidinic compounds (1-4) at the SERT was evaluated by displacement of [H-3]-paroxetine binding. Derived inhibition constant (K-i) values were in the same order of magnitude as that of fluoxetine, ranging between 2 and 400 nM. To better define the profiles of these compounds as potential antidepressants, binding affinity for 5-HT1A receptors and alpha 2-adrenoceptors was also investigated by competition experiments using [H-3]8-hydroxy-2-(dipropylamino)tetralin ([H-3]8-OH-DPAT) and [H-3]rauwolscine as radiolabelled ligands, respectively. Inhibition data indicate that compounds 1-4 possess a very weak affinity for these receptors. The high affinity of compound 1 for SERT indicates that it is worth investigating further.