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.
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.
Weaver
C David
CD
The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Nashville, TN 37232 USA.
Sheffler
Douglas J
DJ
Lewis
L Michelle
LM
Bridges
Thomas M
TM
Williams
Richard
R
Nalywajko
Natalia T
NT
Kennedy
J Phillip
JP
Mulder
Matthew M
MM
Jadhav
Satyawan
S
Aldrich
Leslie A
LA
Jones
Carrie K
CK
Marlo
Joy E
JE
Niswender
Colleen M
CM
Mock
Matthew M
MM
Zheng
Fang
F
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
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*
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