The optimization of a novel selective antagonist for human M muscarinic acetylcholine receptor.
Basic Information
ID: ALA4673268
Journal: Bioorg Med Chem Lett
Title: The optimization of a novel selective antagonist for human M muscarinic acetylcholine receptor.
Authors: Li M,Huang C,Wu X,Ding F,Hu Z,Zhu Y,Zhao L,Hou L,Chen H,Wang H,Xu J,Tang D
Abstract: Muscarinic acetylcholine receptors (mAChRs) comprise five distinct subtypes denoted M to M. The antagonism of M subtype could increase the release of acetylcholine from vesicles into the synaptic cleft and improve postsynaptic functions in the hippocampus via M receptor activation, displaying therapeutic potentials for Alzheimer's disease. However, drug development for M 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 M antagonist, ligand 47, featuring submicromolar IC, high M/M selectivity (~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 ligands.
CiteXplore: 33132116
DOI: 10.1016/j.bmcl.2020.127632
Patent ID: ┄