Synthesis and biological evaluation of meperidine analogues at monoamine transporters

Stacey A. Lomenzo, Jill B. Rhoden, Sari E Izenwasser, Dean Wade, Theresa Kopajtic, Jonathan L. Katz, Mark L. Trudell

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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 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 (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.

Original languageEnglish
Pages (from-to)1336-1343
Number of pages8
JournalJournal of Medicinal Chemistry
Volume48
Issue number5
DOIs
StatePublished - Mar 10 2005

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Meperidine
Opioid Receptors
Ligands
Derivatives
Cocaine
Opioid Analgesics
Dopamine
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Lomenzo, S. A., Rhoden, J. B., Izenwasser, S. E., Wade, D., Kopajtic, T., Katz, J. L., & Trudell, M. L. (2005). Synthesis and biological evaluation of meperidine analogues at monoamine transporters. Journal of Medicinal Chemistry, 48(5), 1336-1343. https://doi.org/10.1021/jm0401614

Synthesis and biological evaluation of meperidine analogues at monoamine transporters. / Lomenzo, Stacey A.; Rhoden, Jill B.; Izenwasser, Sari E; Wade, Dean; Kopajtic, Theresa; Katz, Jonathan L.; Trudell, Mark L.

In: Journal of Medicinal Chemistry, Vol. 48, No. 5, 10.03.2005, p. 1336-1343.

Research output: Contribution to journalArticle

Lomenzo, SA, Rhoden, JB, Izenwasser, SE, Wade, D, Kopajtic, T, Katz, JL & Trudell, ML 2005, 'Synthesis and biological evaluation of meperidine analogues at monoamine transporters', Journal of Medicinal Chemistry, vol. 48, no. 5, pp. 1336-1343. https://doi.org/10.1021/jm0401614
Lomenzo, Stacey A. ; Rhoden, Jill B. ; Izenwasser, Sari E ; Wade, Dean ; Kopajtic, Theresa ; Katz, Jonathan L. ; Trudell, Mark L. / Synthesis and biological evaluation of meperidine analogues at monoamine transporters. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 5. pp. 1336-1343.
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