This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M1). An M1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M1 versus M4. 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 (IC50 = 130 nM) and selective ( > 75-fold vs. M2-M5 and > 10 iM vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (BrainAUC/PlasmaAUC 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 M1 function.
Keywords: Muscarinic, acetylcholine, mAChR, M1, antagonist
Rights & PermissionsPrintExport