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 mu-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 muM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and mu-opioid receptors (mu/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K(i) = 0.125 muM) and was the most selective ligand for the DAT over mu-opioid receptors (mu/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 mu-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
Lomenzo
Stacey A
SA
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA.
Rhoden
Jill B
JB
Izenwasser
Sari
S
Wade
Dean
D
Kopajtic
Theresa
T
Katz
Jonathan L
JL
Trudell
Mark L
ML
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008614:Meperidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017450:Receptors, Opioid, mu; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D008614:Meperidine; D003042:Cocaine