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

Miaomiao Li; Chen Huang; Xingyu Wu; Fan Ding; Zhoumi Hu; Yan Zhu; Lanxue Zhao; Lina Hou; Hongzhuan Chen; Hao Wang; Jianrong Xu; Dewei Tang

doi:10.1016/j.bmcl.2020.127632

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

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127632. doi: 10.1016/j.bmcl.2020.127632. Epub 2020 Oct 24.

Authors

Miaomiao Li¹, Chen Huang², Xingyu Wu³, Fan Ding⁴, Zhoumi Hu⁴, Yan Zhu⁵, Lanxue Zhao¹, Lina Hou¹, Hongzhuan Chen⁶, Hao Wang¹, Jianrong Xu⁷, Dewei Tang⁸

Affiliations

¹ Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
² Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Road, Shanghai 200127, China; College of Medical Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
³ College of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
⁴ Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Road, Shanghai 200127, China.
⁵ School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
⁶ Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
⁷ Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: janker.xu@gmail.com.
⁸ Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Road, Shanghai 200127, China. Electronic address: acetdw@126.com.

PMID: 33132116
DOI: 10.1016/j.bmcl.2020.127632

Abstract

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.

Keywords: Alzheimer’s disease; Antagonist; Muscarinic acetylcholine receptor; Selective; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Humans
Molecular Docking Simulation
Muscarinic Antagonists / chemistry*
Muscarinic Antagonists / pharmacology*
Receptor, Muscarinic M2 / antagonists & inhibitors*
Receptor, Muscarinic M2 / metabolism
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Muscarinic Antagonists
Receptor, Muscarinic M2
Small Molecule Libraries