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选择性毒蕈碱型乙酰胆碱受体亚型1（M1 mAChR）拮抗剂的合成与构效关系

Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists.

作者信息

Lewis L Michelle, Sheffler Douglas, Williams Richard, Bridges Thomas M, Kennedy J Phillip, Brogan J T, Mulder Matthew J, Williams Lyndsey, Nalywajko Natalia T, Niswender Colleen M, Weaver Charles D, Conn P Jeffrey, Lindsley Craig W

机构信息

Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.

出版信息

Bioorg Med Chem Lett. 2008 Feb 1;18(3):885-90. doi: 10.1016/j.bmcl.2007.12.051. Epub 2008 Jan 4.

DOI:10.1016/j.bmcl.2007.12.051
PMID:18178088
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2275053/
Abstract

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.

摘要

本信函描述了通过迭代类似物库方法开发的一系列新型选择性M1毒蕈碱乙酰胆碱受体拮抗剂的合成及其构效关系，这些拮抗剂可用于潜在治疗帕金森病、肌张力障碍和其他运动障碍。该系列化合物的M1拮抗剂IC50值在441 nM至19 μM范围内，相对于rM2 - rM5具有8至>340倍的功能选择性。

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本文引用的文献

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Synthesis, affinity profile, and functional activity of muscarinic antagonists with a 1-methyl-2-(2,2-alkylaryl-1,3-oxathiolan-5-yl)pyrrolidine structure.具有1-甲基-2-(2,2-烷基芳基-1,3-氧杂硫杂环戊烷-5-基)吡咯烷结构的毒蕈碱拮抗剂的合成、亲和力谱及功能活性
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Preclinical drug discovery research and training at Vanderbilt.范德堡大学的临床前药物发现研究与培训。
ACS Chem Biol. 2007 Jan 23;2(1):17-20. doi: 10.1021/cb6004867.
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Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries.开发用于化合物库制备纯化和分析分析的定制高通量制备液相色谱/质谱仪平台。
J Comb Chem. 2003 May-Jun;5(3):322-9. doi: 10.1021/cc0201041.
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Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system.利用M1 - M5毒蕈碱受体基因敲除小鼠作为新型工具来阐明毒蕈碱胆碱能系统的生理作用。
Neurochem Res. 2003 Apr;28(3-4):437-42. doi: 10.1023/a:1022844517200.
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Therapeutic opportunities for muscarinic receptors in the central nervous system.中枢神经系统中毒蕈碱受体的治疗机会。
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Curr Opin Chem Biol. 1999 Aug;3(4):426-32. doi: 10.1016/S1367-5931(99)80063-5.
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Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors: functional studies.马钱子碱类似物与毒蕈碱受体处乙酰胆碱之间的亚型选择性正协同相互作用：功能研究
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The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease.选择性毒蕈碱激动剂占诺美林可改善阿尔茨海默病的认知缺陷和行为症状。
Alzheimer Dis Assoc Disord. 1997;11 Suppl 4:S16-22.
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Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.选择性毒蕈碱受体激动剂占诺美林对阿尔茨海默病认知功能和行为症状的影响。
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