Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: Effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors

Rong He, Toru Kurome, Kelly M. Giberson, Kenneth M. Johnson, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

4-(4-Chlorophenyl)piperidine analogues each bearing a thioacetamide side chain appendage similar to that found in the wake-promoting drug modafinil have been synthesized. The transporter inhibitory activity of both the cis and trans isomers of these 3,4-disubstituted piperidines in both their (+)- and (-)-enantiomeric forms was determined. These studies reveal that the (-)-cis analogues exhibit dopamine transporter/norepinephrine transporter (DAT/ NET) selectivity as was previously reported for the (+)-trans analogues. On the other hand, the (-)-trans and the (+)-cis isomers show serotonin transporter (SERT) or SERT/NET selectivity. Among them, (+)-cis-5b shows a low nanomolar K i for the NET with 39-fold and 321-fold lower potency at the DAT and SERT, respectively, thus making it a useful pharmacological research tool for exploring NET-associated behavioral signatures. On the other hand, several of the compounds described herein, such as (+)-trans-5c, show comparable activity at all three transporters. Because broad-spectrum transporter inhibitors have been hypothesized to exhibit a more rapid onset of action and/or a greater efficacy as antidepressant agents than those selective for SERT or SERT + NET, some of the present compounds will be valuable to study in animal models of depression.

Original languageEnglish (US)
Pages (from-to)7970-7979
Number of pages10
JournalJournal of medicinal chemistry
Volume48
Issue number25
DOIs
StatePublished - Dec 15 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: Effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors'. Together they form a unique fingerprint.

Cite this