The optimization of a novel selective antagonist for human M2 muscarinic acetylcholine receptor

• Published in: Bioorganic & medicinal chemistry letters 2020-12, Vol.30 (24), p.127632-127632, Article 127632
• Main Authors: Li, Miaomiao, Huang, Chen, Wu, Xingyu, Ding, Fan, Hu, Zhoumi, Zhu, Yan, Zhao, Lanxue, Hou, Lina, Chen, Hongzhuan, Wang, Hao, Xu, Jianrong, Tang, Dewei
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Antagonist; Muscarinic acetylcholine receptor; Selective; Structure–activity relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127632

[Display omitted] •A new scaffold for M2 antagonist was discovered from virtual screening and optimized.•Novel M2 antagonist, ligand 47, displayed submicromolar IC50, high M2/M4 selectivity (~30-fold).•The structure–activity relationship of this novel scaffold was investigated with 3D-QSAR and docking. Muscarinic acetylcholine receptors (mAChRs) comprise five distinct subtypes denoted M1 to M5. The antagonism of M2 subtype could increase the release of acetylcholine from vesicles into the synaptic cleft and improve postsynaptic functions in the hippocampus via M1 receptor activation, displaying therapeutic potentials for Alzheimer’s disease. However, drug development for M2 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 M2/M4 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 M2 ligands.