Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists

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 IC50s in the 441 nM–19 μM range with 8- to >340-fold functional selectivity versus rM2–rM5.

The synthesis and SAR of selective rM1 antagonists, such as 9g (>45-fold selective versus rM2–rM5) and 9i (>340-fold selective versus rM4), are described as part of a chemical probe development program for the Molecular Library Screening Network.Figure optionsDownload as PowerPoint slide