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

Autor:	Ivar M. McDonald, Robert A. Mate, Debra J. Post-Munson, Meredith Ferrante, David G. Harden, Lizbeth Gallagher, Richard E. Olson, F. Christopher Zusi, Barbara J. Robertson, Steven I. Dworetzky, Daniel G. Morgan, Hong Huang, Ronald J. Knox, Nicholas J. Lodge, John E. Macor, Robert L. Bertekap
Rok vydání:	2013
Předmět:	alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class High-throughput screening Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Quinolones Receptors Nicotinic Pharmacology Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Humans Structure–activity relationship Moiety Nicotinic Agonists Molecular Biology Organic Chemistry Quinolone Rats Kinetics Nicotinic agonist chemistry Molecular Medicine Efflux Caco-2 Cells Alpha-4 beta-2 nicotinic receptor Quinuclidine
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 23:1684-1688
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9746d0f86cd20debcb9cc92ebb146599 https://doi.org/10.1016/j.bmcl.2013.01.070 Zobrazit plný text záznamu Full Text from ScienceDirect