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The optimization of a novel selective antagonist for human M2 muscarinic acetylcholine receptor
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-10-24 , DOI: 10.1016/j.bmcl.2020.127632
Miaomiao Li 1 , Chen Huang 2 , Xingyu Wu 3 , Fan Ding 4 , Zhoumi Hu 4 , Yan Zhu 5 , Lanxue Zhao 1 , Lina Hou 1 , Hongzhuan Chen 6 , Hao Wang 1 , Jianrong Xu 7 , Dewei Tang 4
Affiliation  

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.



中文翻译:

新型人M 2毒蕈碱乙酰胆碱受体选择性拮抗剂的优化

毒蕈碱型乙酰胆碱受体(mAChRs)包含五个不同的亚型,表示为M 1至M 5。M 2亚型的拮抗作用可通过M 1受体激活增加乙酰胆碱从囊泡向突触间隙的释放并改善海马突触后功能,从而显示出治疗阿尔茨海默氏病的潜力。但是,M 2拮抗剂的药物开发仍在不同的受体亚型中受到挑战。在这项研究中,通过优化虚拟筛选的支架,我们合成了两个聚焦库并生成了多达50个衍生物。通过测量效能和结合选择性,我们发现了新型M 2拮抗剂,配体47,具有亚微摩尔IC 50,高M 2 / M 4选择性(〜30倍)和合适的亲脂性(cLogP = 4.55)。对这些化合物的进一步研究也说明了这种新型支架的结构-活性关系。我们的研究不仅可以提供易于合成的新颖的先导结构,而且还为进一步开发选择性M 2配体提供了有价值的信息。

更新日期:2020-10-30
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