title: Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective α4β2-nAChR Ligands.
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 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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Oluseye K
authors.initials: OK
authors.lastname: Onajole
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute , 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute , 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.affiliation: PsychoGenics, Inc. , 765 Old Saw Mill River Road, Tarrytown, New York 10591, United States.
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
authors.affiliation: PsychoGenics, Inc. , 765 Old Saw Mill River Road, Tarrytown, New York 10591, United States.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Thiede
authors.affiliation: NeuroBehavior Laboratory, Harvard NeuroDiscovery Center and Department of Neurology, Brigham and Women's Hospital , 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Caldarone
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
keywords: N-pyridyldiazabicyclo[3.3.0]octane; Nicotinic acetylcholine receptor; selective α4β2 partial agonist