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 journalArticle

Abstract

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
Volume5
Issue number11
DOIs
StatePublished - Nov 13 2014
Externally publishedYes

Fingerprint

Octanes
Bearings (structural)
Nicotinic Receptors
Assays
Ligands
Antidepressive Agents
Anti-Anxiety Agents
Structure-Activity Relationship
Antipsychotic Agents
cyclopropane

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Onajole, O. K., Eaton, J. B., Lukas, R. J., Brunner, D., Thiede, L., Caldarone, B. J., & Kozikowski, A. P. (2014). Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands. ACS Medicinal Chemistry Letters, 5(11), 1196-1201. https://doi.org/10.1021/ml500129k

Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands. / Onajole, Oluseye K.; Eaton, J. Brek; Lukas, Ronald J.; Brunner, Dani; Thiede, Lucinda; Caldarone, Barbara J.; Kozikowski, Alan P.

In: ACS Medicinal Chemistry Letters, Vol. 5, No. 11, 13.11.2014, p. 1196-1201.

Research output: Contribution to journalArticle

Onajole, OK, Eaton, JB, Lukas, RJ, Brunner, D, Thiede, L, Caldarone, BJ & Kozikowski, AP 2014, 'Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands', ACS Medicinal Chemistry Letters, vol. 5, no. 11, pp. 1196-1201. https://doi.org/10.1021/ml500129k
Onajole, Oluseye K. ; Eaton, J. Brek ; Lukas, Ronald J. ; Brunner, Dani ; Thiede, Lucinda ; Caldarone, Barbara J. ; Kozikowski, Alan P. / Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 11. pp. 1196-1201.
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