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

Abstract

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 [3H]-paroxetine binding. Derived inhibition constant (Ki) 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 α2-adrenoceptors was also investigated by competition experiments using [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT) and [3H]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.