2,3-Disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors

Josefina Quirante, Xavier Vila, Josep Bonjoch, Alan P. Kozikowski, Kenneth M. Johnson

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

A series of cis and trans 3β-aryl-2-carbomethoxy-6-azabicyclo[3.2.1] octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the β-aryl group, IC50=452 nM) displayed a potency that is in the same range as cocaine (IC50=459 nM) itself.

Original languageEnglish
Pages (from-to)1383-1391
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number6
DOIs
StatePublished - Mar 15 2004

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Cocaine
Inhibitory Concentration 50
Bearings (structural)
Tropanes
Scaffolds
Amines
Substitution reactions
Ligands
6-azabicyclo(3.2.1)octane

Keywords

  • 6-Azabicyclo[3.2.1]octane
  • Cocaine
  • Dopamine uptake
  • Normorphan analogues

ASJC Scopus subject areas

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

Cite this

2,3-Disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors. / Quirante, Josefina; Vila, Xavier; Bonjoch, Josep; Kozikowski, Alan P.; Johnson, Kenneth M.

In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 6, 15.03.2004, p. 1383-1391.

Research output: Contribution to journalArticle

Quirante, Josefina ; Vila, Xavier ; Bonjoch, Josep ; Kozikowski, Alan P. ; Johnson, Kenneth M. / 2,3-Disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors. In: Bioorganic and Medicinal Chemistry. 2004 ; Vol. 12, No. 6. pp. 1383-1391.
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