Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective ?4?2-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 ?4?2-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 ?2 subunit-containing nAChR subtypes (?2*-nAChRs) over ?4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for ?4?2- and ?4?2*-nAChRs with negligible interaction. Functional assays confirm selectivity for ?4?2-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.

SUBMITTER: Onajole OK 

PROVIDER: S-EPMC4233362 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature