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.

Weaver CD, Sheffler DJ, Lewis LM, Bridges TM, Williams R, Nalywajko NT, Kennedy JP, Mulder MM, Jadhav S, Aldrich LA, Jones CK, Marlo JE, Niswender CM, Mock MM, Zheng F, Conn PJ, Lindsley CW
Curr Top Med Chem. 2009 9 (13): 1217-26

PMID: 19807667 · PMCID: PMC4765323 · DOI:10.2174/156802609789753635

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.

MeSH Terms (6)

Drug Discovery High-Throughput Screening Assays Receptor, Muscarinic M1 Substrate Specificity Sulfonamides Thiadiazoles

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