title: 4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor.
abstract: Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer's and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Shailesh N
authors.initials: SN
authors.lastname: Mistry
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Manuela
authors.initials: M
authors.lastname: Jörg
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Herman
authors.initials: H
authors.lastname: Lim
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Natalie B
authors.initials: NB
authors.lastname: Vinh
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D016466:CHO Cells; D003072:Cognition Disorders / Q000188:drug therapy; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D011869:Radioligand Assay; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: C583161:1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; C000607646:4-phenylpyridin-2-one; D018721:Muscarinic Agonists; D011728:Pyridones; D011804:Quinolines; D043643:Receptor, Muscarinic M1; D000109:Acetylcholine