title: Synthesis and pharmacological evaluation of analogues of benzyl quinolone carboxylic acid (BQCA) designed to bind irreversibly to an allosteric site of the M ₁ muscarinic acetylcholine receptor.
abstract: Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Briana J
authors.initials: BJ
authors.lastname: Davie
authors.forename: Celine
authors.initials: C
authors.lastname: Valant
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
mesh_terms: D000495:Allosteric Site; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D017879:Isothiocyanates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000591354:1-(4-isothiocyanatobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D017879:Isothiocyanates; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3