Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]Octanes As Selective α4β2-Nachr Ligands
Department
neurobiology
Document Type
Article
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.
Publication Date
11-13-2014
Publication Title
ACS Medicinal Chemistry Letters
ISSN
19485875
Volume
5
Issue
11
First Page
1196
Last Page
1201
Digital Object Identifier (DOI)
10.1021/ml500129k
Recommended Citation
Onajole, Oluseye K.; Eaton, J. Brek; Lukas, Ronald J.; Brunner, Dani; Thiede, Lucinda; Caldarone, Barbara J.; and Kozikowski, Alan P., "Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]Octanes As Selective α4β2-Nachr Ligands" (2014). Translational Neuroscience. 218.
https://scholar.barrowneuro.org/neurobiology/218