Open AccessEnantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective α4β2-nAChR Ligands
Author(s) -
Oluseye K. Onajole,
J. Brek Eaton,
Ronald J. Lukas,
Dani Brunner,
Lucinda Thiede,
Barbara J. Caldarone,
Alan P. Kozikowski
Publication year - 2014
Publication title -
acs medicinal chemistry letters
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml500129k
Subject(s) - cyclopropane , chemistry , stereochemistry , nicotinic acetylcholine receptor , enantiopure drug , nicotinic agonist , acetylcholine receptor , ligand (biochemistry) , selectivity , ring (chemistry) , receptor , biochemistry , enantioselective synthesis , organic chemistry , catalysis
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 β4*-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.
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