Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists.
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(1H)-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 pKa. A novel 4-fluoroquinuclidine significantly lowered the pKa of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay.
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GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y
α7 nicotinic acetylcholine receptor 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one 4-fluoroquinuclidine quinuclidine quinolone acetylcholine quinolone acetylcholine nAChR α7 nicotinic acetylcholine receptor