title: 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(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.
authors: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. ivar.mcdonald@bms.com
authors: Ivar M
authors: IM
authors: McDonald
authors: Robert A
authors: RA
authors: Mate
authors: F Christopher
authors: FC
authors: Zusi
authors: Hong
authors: H
authors: Huang
authors: Debra J
authors: DJ
authors: Post-Munson
authors: Meredith A
authors: MA
authors: Ferrante
authors: Lizbeth
authors: L
authors: Gallagher
authors: Robert L
authors: RL
authors: Bertekap
authors: Ronald J
authors: RJ
authors: Knox
authors: Barbara J
authors: BJ
authors: Robertson
authors: David G
authors: DG
authors: Harden
authors: Daniel G
authors: DG
authors: Morgan
authors: Nicholas J
authors: NJ
authors: Lodge
authors: Steven I
authors: SI
authors: Dworetzky
authors: Richard E
authors: RE
authors: Olson
authors: John E
authors: JE
authors: Macor
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D015363:Quinolones; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor