title: Discovery and development of a potent and highly selective small molecule muscarinic acetylcholine receptor subtype I (mAChR 1 or M1) antagonist in vitro and in vivo probe.
abstract: This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M(1)). An M(1) functional, cell-based calcium-mobilization assay identified three distinct chemical series with initial selectivity for M(1) versus M(4). An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC(50) = 130 nM) and selective (>75-fold vs. M(2)-M(5) and > 10 microM vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M(1) antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (Brain(AUC)/Plasma(AUC) of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/ MLPCN probe molecule for studying and dissecting M(1) function.
authors.affiliation: The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Nashville, TN 37232 USA.
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: L Michelle
authors.initials: LM
authors.lastname: Lewis
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Natalia T
authors.initials: NT
authors.lastname: Nalywajko
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kennedy
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Mulder
authors.forename: Satyawan
authors.initials: S
authors.lastname: Jadhav
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Aldrich
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Joy E
authors.initials: JE
authors.lastname: Marlo
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Mock
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C542801:N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide; D043643:Receptor, Muscarinic M1; D013449:Sulfonamides; D013830:Thiadiazoles