Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 6, Pages 941-948Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00106
Keywords
Muscarinic acetylcholine receptor; M4 mAChR; selective mAChR agonist; carbamate isosteres; electrostatic potential isosurface; ensemble docking
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It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor agonist interaction mode.
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