Further structure-activity relationship studies on 8-substituted-3-[2- (diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

Shaine A. Cararas, Sari Izenwasser, Dean Wade, Amy Housman, Abha Verma, Stacey A. Lomenzo, Mark L. Trudell

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


The synthesis and structure-activity relationships of 8-substituted-3-[2- (diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives were investigated at the dopamine transporter (DAT), the serotonin transporter (SERT) and norepinephrine transporter (NET). The rigid ethylidenyl-8-azabicyclic[3.2. 1]octane skeleton imparted modestly stereoselective binding and uptake inhibition at the DAT. Additional structure-activity studies provided a transporter affinity profile that was reminiscent of the structure-activity of GBR 12909. From these studies, the 8-cyclopropylmethyl group has been identified as a unique moiety that imparts high SERT/DAT selectivity. In this study the 8-cyclopropylmethyl derivative 22e (DAT K i of 4.0 nM) was among the most potent compounds of the series at the DAT and was the most DAT selective ligand of the series (SERT/DAT: 1060). Similarly, the 8-chlorobenzyl derivative 22g (DAT K i of 3.9 nM) was found to be highly selective for the DAT over the NET (NET/DAT: 1358).

Original languageEnglish (US)
Pages (from-to)7551-7558
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number24
StatePublished - Dec 15 2011


  • Cocaine
  • Dopamine transporter
  • Dopamine uptake
  • GBR 12909
  • Norepinephrine transporter
  • Serotonin transporter
  • Tropane

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry


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