Synthesis and radioligand binding studies of C-5- and C-8-substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums as SK channel blockers related to N-methyl-laudanosine and N-methyl-noscapine
Synthesis and radioligand binding studies of C-5- and C-8-substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums as SK channel blockers related to N-methyl-laudanosine and N-methyl-noscapine
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DOI：
10.1021/jm049025p
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发表时间：
2005-07-28
影响因子：
7.3
通讯作者：
Liégeois, JF
中科院分区：
文献类型：
--
作者：
Graulich, A;Scuvée-Moreau, J;Liégeois, JF
本文报道了C-5和C-8取代的143，4-二甲氧基苄基）-2，2-二甲基-1，2，3，4-四氢异喹啉鎓和1-（3，4-二甲氧基-苄基）-6，6-二甲基-4，5，6，7-四氢噻吩并[2，3-c]吡啶鎓进行，以找到结构上与N-甲基-劳丹核苷和N-甲基-诺斯卡品相关的可逆的和选择性的SK通道阻断剂。在四氢异喹啉的C-8位上的大体积烷基取代基产生对apamin敏感结合位点的亲和力的明显增加。在C-5和C-8位置上存在吸电子基团对于结构上与N-甲基-劳丹核苷相关的药物的亲和力不是合适的替代。噻吩类似物和8-甲氧基衍生物对蜂毒肽敏感的结合位点具有较差的亲和力。用最有效的化合物进行的电生理学研究表明，在大鼠多巴胺能神经元中阻断了apamin敏感的后超极化。
The synthesis and the 125 I-apamin binding studies of original C-5- and C-8-substituted 143,4-dimethoxy-benzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums and 1-(3,4-dimethoxy-benzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridiniums were performed in order to find a reversible and selective SK channel blocker structurally related to N-methyl-laudanosine and N-methyl-noscapine. A bulky alkyl substituent in the C-8 position of the tetrahydroisoquinoline produces a clear increase in the affinity for the apamin sensitive binding sites. The presence of an electron-withdrawing group in the C-5 and C-8 positions is not a suitable substitution for the affinity of drugs structurally related to N-methyl-laudanosine. Thiophenic analogues and 8-methoxy derivatives possess a poor affinity for the apamin sensitive binding sites. Electrophysiological studies performed with the most effective compound showed a blockade of the apamin sensitive afterhyperpolarization in rat dopaminergic neurons.