Synthesis and Biological Evaluation of Meperidine Analogues at Monoamine Transporters
Stacey A. Lomenzo, Jill B. Rhoden, Sari Izenwasser, Dean Wade, Theresa Kopajtic, Jonathan L. Katz, and Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, Florida 33136, and Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, Maryland 21224
Received September 2, 2004
Abstract:
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 -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 M) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and -opioid receptors (/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (Ki = 0.125 M) and was the most selective ligand for the DAT over -opioid receptors (/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 -opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
