Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors.
Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors.
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DOI：
10.3389/fphar.2020.552211
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发表时间：
2020
影响因子：
5.6
通讯作者：
Brenner R
中科院分区：
文献类型：
--
作者：
Bugay V;Wallace DJ;Wang B;Salinas I;Chapparo AP;Smith HR;Dube PH;Brooks EG;Berg KA;Brenner R
Dequalinium被用作口腔健康和其他微生物感染的抗菌化合物。去qualinium的衍生物，双喹啉环烷UCL 1684和UCL 1848，是高亲和的SK钾通道拮抗剂。本文研究了这些化合物作为M3毒蕈碱受体（mACHR）拮抗剂的作用。我们使用R-CEPIAer内质网钙报告基因对gq偶联受体信号进行功能检测，并研究了双喹啉环烷作为转染CHO细胞中M3 mACHR激活的拮抗剂。考虑到mACHR在气道平滑肌（ASM）收缩中的作用，我们还测试了UCL 1684放松ASM的能力。我们发现这些化合物对M3 mACHRs的拮抗作用，对脱氯、对UCL 1684和对UCL 1848的IC50分别为0.27 μM、1.5 μM和1.0 μM。ucl1684还能拮抗M1 （IC50 0.12 μM）和M5 （IC50 0.52 μM）的mACHR反应。UCL 1684被确定为M3受体的竞争性拮抗剂，因为它增加了碳苯酚的EC50，而没有降低最大反应。通过竞争结合实验确定UCL1684的Ki值为909 nM。ucl1684降低了碳巴酚引起的肌浆收缩（>90%,IC50 0.43 μM），降低了鼠和人肺肌浆细胞的钙动员。我们得出结论，在亚至低微摩尔浓度下，脱喹啉和双喹啉环番可拮抗M3 mACHR的激活，ucl1684可作为ASM松弛剂。当使用这些化合物阻断SK钾通道时应谨慎，因为如果使用浓度过高，可能会产生抑制machr的副作用。
Dequalinium is used as an antimicrobial compound for oral health and other microbial infections. Derivatives of dequalinium, the bis-quinolinium cyclophanes UCL 1684 and UCL 1848, are high affinity SK potassium channel antagonists. Here we investigated these compounds as M3 muscarinic receptor (mACHR) antagonists. We used the R-CEPIAer endoplasmic reticulum calcium reporter to functionally assay for Gq-coupled receptor signaling, and investigated the bis-quinolinium cyclophanes as antagonists of M3 mACHR activation in transfected CHO cells. Given mACHR roles in airway smooth muscle (ASM) contractility, we also tested the ability of UCL 1684 to relax ASM. We find that these compounds antagonized M3 mACHRs with an IC50 of 0.27 μM for dequalinium chloride, 1.5 μM for UCL 1684 and 1.0 μM for UCL 1848. UCL 1684 also antagonized M1 (IC50 0.12 μM) and M5 (IC50 0.52 μM) mACHR responses. UCL 1684 was determined to be a competitive antagonist at M3 receptors as it increased the EC50 for carbachol without a reduction in the maximum response. The Ki for UCL1684 determined from competition binding experiments was 909 nM. UCL 1684 reduced carbachol-evoked ASM contractions (>90%, IC50 0.43 μM), and calcium mobilization in rodent and human lung ASM cells. We conclude that dequalinium and bis-quinolinium cyclophanes antagonized M3 mACHR activation at sub- to low micromolar concentrations, with UCL 1684 acting as an ASM relaxant. Caution should be taken when using these compounds to block SK potassium channels, as inhibition of mACHRs may be a side-effect if excessive concentrations are used.
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影响因子：
2.5
作者：
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通讯作者：
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通讯作者：
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