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

…, DJ Post-Munson, MA Ferrante, L Gallagher…

Index: McDonald, Ivar M.; Mate, Robert A.; Zusi, F. Christopher; Huang, Hong; Post-Munson, Debra J.; Ferrante, Meredith A.; Gallagher, Lizbeth; Bertekap Jr., Robert L.; Knox, Ronald J.; Robertson, Barbara J.; Harden, David G.; Morgan, Daniel G.; Lodge, Nicholas J.; Dworetzky, Steven I.; Olson, Richard E.; MacOr, John E. Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 6 p. 1684 - 1688

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Citation Number: 8

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 ...