title: Development of a photoactivatable allosteric ligand for the m1 muscarinic acetylcholine receptor.
abstract: The field of G protein-coupled receptor drug discovery has benefited greatly from the structural and functional insights afforded by photoactivatable ligands. One G protein-coupled receptor subfamily for which photoactivatable ligands have been developed is the muscarinic acetylcholine receptor family, though, to date, all such ligands have been designed to target the orthosteric (endogenous ligand) binding site of these receptors. Herein we report the synthesis and pharmacological investigation of a novel photoaffinity label, MIPS1455 (4), designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor; a target of therapeutic interest for the treatment of cognitive deficits. MIPS1455 may be a valuable molecular tool for further investigating allosteric interactions at this receptor.
authors.affiliation: Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Briana J
authors.initials: BJ
authors.lastname: Davie
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; D001577:Benzophenones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D018678:Cholinergic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010782:Photolysis; D015363:Quinolones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: C000599365:1-(4-benzoylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D001577:Benzophenones; D018678:Cholinergic Agents; D008024:Ligands; D019920:Photoaffinity Labels; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: BQCA; Muscarinic; allosteric; cognition; photoactivatable; photoaffinity