From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue.
From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue.
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DOI：
10.1021/acs.jmedchem.2c00746
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发表时间：
2022-07-28
影响因子：
7.3
通讯作者：
Bolchi, Cristiano
中科院分区：
文献类型：
--
作者：
Bavo, Francesco;Pallavicini, Marco;Pucci, Susanna;Appiani, Rebecca;Giraudo, Alessandro;Eaton, Brek;Lucero, Linda;Gotti, Cecilia;Moretti, Milena;Whiteaker, Paul;Bolchi, Cristiano
含有α9亚基的尼古丁乙酰胆碱受体（α9*-nAChRs）是替代阿片类药物治疗疼痛的潜在药物靶点。非肽小分子选择性地作为α9*-nAChRs拮抗剂仍然是一个未实现的目标。本文通过阳离子头和乙烯连接剂的修饰，将众所周知的α7-和α9*- nachr拮抗剂- 2-三乙基乙醚- 4-己烯醇（MG624）转化为人类α9*- nachr的选择性拮抗剂。其中，具有环己基二甲基铵头(7)的化合物具有α7- nachr的激动剂和拮抗剂作用，对α7-和α3β4- nachr的亲和力都很低。在超微摩尔浓度下，7和其他选择性α9*拮抗剂在α9*- nachr上表现为部分激动剂，反应非常短暂，一旦停止应用，通道脱离，就会产生反弹电流。施后乙酰胆碱活性小或为零似乎与回跳电流恢复缓慢有关。
Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest for pain treatment alternative to opioids. Nonpeptidic small molecules selectively acting as α9*-nAChRs antagonists still remain an unattained goal. Here, through modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known α7- and α9*-nAChRs antagonist, into some selective antagonists of human α9*-nAChR. Among these, the compound with cyclohexyldimethylammonium head (7) stands out for having no α7-nAChR agonist or antagonist effect along with very low affinity at both α7- and α3β4-nAChRs. At supra-micromolar concentrations, 7 and the other selective α9* antagonists behaved as partial agonists at α9*-nAChRs with a very brief response, followed by rebound current once the application is stopped and the channel is disengaged. The small or null postapplication activity of ACh seems to be related to the slow recovery of the rebound current.
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影响因子：
16.2
作者：
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通讯作者：
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影响因子：
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Morley BJ;Whiteaker P;Elgoyhen AB
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Elgoyhen AB
影响因子：
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