Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-02-14 DOI:10.1021/acsbiomedchemau.2c00057

Ashraf M. A. Qasem, Michael G. Rowan, Victoria R. Sanders, Neil S. Millar and Ian S. Blagbrough*,

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引用次数: 2

Abstract

Methyllycaconitine (MLA), 1, is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC₅₀ = 2 nM) selective antagonist of α7 nicotinic acetylcholine receptors (nAChRs). Several structural factors affect its activity such as the neopentyl ester side-chain and the piperidine ring N-side-chain. The synthesis of simplified AE-bicyclic analogues 14–21 possessing different ester and nitrogen side-chains was achieved in three steps. The antagonist effects of synthetic analogues were examined on human α7 nAChRs and compared to that of MLA 1. The most efficacious analogue (16) reduced α7 nAChR agonist responses [1 nM acetylcholine (ACh)] to 53.2 ± 1.9% compared to 3.4 ± 0.2% for MLA 1. This demonstrates that simpler analogues of MLA 1 possess antagonist effects on human α7 nAChRs but also indicates that further optimization may be possible to achieve antagonist activity comparable to that of MLA 1.

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甲基莱卡乌碱类似物的合成及其对人α - 7烟碱乙酰胆碱受体的拮抗活性

甲基下乌头碱（MLA），1，是一种天然存在的去甲二萜生物碱，是α7烟碱型乙酰胆碱受体（nAChRs）的高效（IC50=2nM）选择性拮抗剂。影响其活性的几个结构因素，如新戊酯侧链和哌啶环N-侧链。通过三个步骤合成了具有不同酯和氮侧链的简化AE双环类似物14-21。研究了合成类似物对人α7nAChRs的拮抗作用，并与MLA1的拮抗作用进行了比较。最有效的类似物（16）将α7-nAChR激动剂反应[1nM乙酰胆碱（ACh）]降低到53.2±1.9%，而MLA1为3.4±0.2%。这表明MLA1的更简单的类似物对人α7nAChRs具有拮抗作用，但也表明进一步优化可能实现与MLA1相当的拮抗活性。

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ACS Bio & Med Chem Au 药物、生物、化学-

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4.10

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0.00%

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期刊介绍： ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.

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