The Optimization Of A Novel Selective Antagonist For Human M-2 Muscarinic Acetylcholine Receptor

Muscarinic acetylcholine receptors (mAChRs) comprise five distinct subtypes denoted M-1 to M-5. The antagonism of M-2 subtype could increase the release of acetylcholine from vesicles into the synaptic cleft and improve postsynaptic functions in the hippocampus via M-1 receptor activation, displaying therapeutic potentials for Alzheimer's disease. However, drug development for M-2 antagonists is still challenged among different receptor subtypes. In this study, by optimizing a scaffold from virtual screening, we synthesized two focused libraries and generated up to 50 derivatives. By measuring potency and binding selectivity, we discovered a novel M2 antagonist, ligand 47, featuring submicromolar IC50, high M-2/M-4 selectivity (similar to 30-fold) and suitable lipophilicity (cLogP = 4.55). Further study with these compounds also illustrates the structure-activity relationship of this novel scaffold. Our study could not only provide novel lead structure, which was easy to synthesize, but also offer valuable information for further development of selective M-2 ligands.