title: Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists.
abstract: This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.
authors.affiliation: Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
authors.forename: L Michelle
authors.initials: LM
authors.lastname: Lewis
authors.forename: Douglas
authors.initials: D
authors.lastname: Sheffler
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kennedy
authors.forename: J T
authors.initials: JT
authors.lastname: Brogan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Mulder
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Williams
authors.forename: Natalia T
authors.initials: NT
authors.lastname: Nalywajko
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Charles D
authors.initials: CD
authors.lastname: Weaver
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic