jm0401614_si_001.pdf (36.46 kB)
Synthesis and Biological Evaluation of Meperidine Analogues at Monoamine Transporters
journal contribution
posted on 2005-03-10, 00:00 authored by Stacey A. Lomenzo, Jill B. Rhoden, Sari Izenwasser, Dean Wade, Theresa Kopajtic, Jonathan L. Katz, Mark L. TrudellA 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 (Ki = 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 (Ki = 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.