Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists

Abstract High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit ( 1 ) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1 H )-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high p K a . A novel 4-fluoroquinuclidine significantly lowered the p K a of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay.