Subnanomolar Affinity and Selective Antagonism at α7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624).
Subnanomolar Affinity and Selective Antagonism at α7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624).
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DOI：
10.1021/acs.jmedchem.2c01256
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发表时间：
2023-01-12
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;Oh, Hyoungil;Kneisley, Dana L.;Eaton, Brek;Lucero, Linda;Gotti, Cecilia;Clementi, Francesco;Whiteaker, Paul;Bolchi, Cristiano
已证明对4-芪酚的2-（三乙基铵）乙基醚（MG 624）的阳离子头部和乙烯连接基的修饰产生选择性α9*-nAChR拮抗作用，而对α7-亚型没有任何影响。在此，MG 624苯乙烯基部分的单一结构变化导致α7-nAChR拮抗作用占优势，而不消除α9*-nAChR拮抗作用。尽管如此，如果包括氢键供体NH，如5-吲哚基（31），则苯乙烯基硬化为芳香族双环，导致更高和更有选择性的α7-nAChR亲和力。将这种修饰与2-三乙基铵甲氧基部分限制性地杂交到（R）-N，N-二甲基-3-吡咯烷肟基亚结构中，先前报道为MG 624的α7-nAChR亲和力的最佳修饰（2），是一种成功的策略。产生的杂交体33具有亚纳摩尔的α7-nAChR亲和力，并且是有效的和选择性的α7-nAChR拮抗剂，在α7-nAChR处产生，而不是在α9*-nAChR处，导致随后的ACh功能的严重丧失。
Modifications of the cationic head and the ethylene linker of 2-(triethylammonium)ethyl ether of 4-stilbenol (MG624) have been proved to produce selective α9*-nAChR antagonism devoid of any effect on the α7-subtype. Here, single structural changes at the styryl portion of MG624 lead to prevailing α7-nAChR antagonism without abolishing α9*-nAChR antagonism. Nevertheless, rigidification of the styryl into an aromatic bicycle, better if including a H-bond donor NH, such as 5-indolyl (31), resulted in higher and more selective α7-nAChR affinity. Hybridization of this modification with the constraint of the 2-triethylammoniumethyloxy portion into (R)-N,N-dimethyl-3-pyrrolidiniumoxy substructure, previously reported as the best modification for the α7-nAChR affinity of MG624 (2), was a winning strategy. The resulting hybrid 33 had a subnanomolar α7-nAChR affinity and was a potent and selective α7-nAChR antagonist, producing at the α7-, but not at the α9*-nAChR, a profound loss of subsequent ACh function.
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影响因子：
7.3
作者：
Bavo, Francesco;Pallavicini, Marco;Pucci, Susanna;Appiani, Rebecca;Giraudo, Alessandro;Eaton, Brek;Lucero, Linda;Gotti, Cecilia;Moretti, Milena;Whiteaker, Paul;Bolchi, Cristiano
通讯作者：
Bolchi, Cristiano
影响因子：
--
作者：
De Filippis, Barbara;Agamennone, Mariangela;Amoroso, Rosa
通讯作者：
Amoroso, Rosa
影响因子：
16.2
作者：
Gu, Shenyan;Matta, Jose A.;Bredt, David S.
通讯作者：
Bredt, David S.
影响因子：
3.6
作者：
Haghbeen, K;Tan, EW
通讯作者：
Tan, EW
影响因子：
7.3
作者：
Bavo, Francesco;Pucci, Susanna;Pallavicini, Marco
通讯作者：
Pallavicini, Marco