Synthesis and biological evaluation of meperidine analogues at monoamine transporters

A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at μ-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (K_i = 0.0072 μM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and μ-opioid receptors (μ/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K _i = 0.125 μM) and was the most selective ligand for the DAT over μ-opioid receptors (μ/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the μ-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.