Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands

Oluseye K. Onajole, J. Brek Eaton, Ronald J. Lukas, Dani Brunner, Lucinda Thiede, Barbara J. Caldarone, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR β2 subunit-containing nAChR subtypes (β2∗-nAChRs) over α4∗-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2-and α4β2∗-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15.

Original languageEnglish (US)
Pages (from-to)1196-1201
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number11
StatePublished - Nov 13 2014


  • N-pyridyldiazabicyclo[3.3.0]octane
  • Nicotinic acetylcholine receptor
  • selective α4β2 partial agonist

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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