BINDING OF ARYLPIPERAZINES TO 5-HT3 SEROTONIN RECEPTORS - RESULTS OF A STRUCTURE-AFFINITY STUDY
BINDING OF ARYLPIPERAZINES TO 5-HT3 SEROTONIN RECEPTORS - RESULTS OF A STRUCTURE-AFFINITY STUDY
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DOI：
10.1016/0014-2999(89)90802-9
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发表时间：
1989-09-22
影响因子：
5
通讯作者：
PEROUTKA, SJ
中科院分区：
文献类型：
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作者：
GLENNON, RA;ISMAIEL, AEM;PEROUTKA, SJ
研究了一系列芳基哌嗪衍生物在[3H]喹嗪标记的中心5-HT3位点上的结合亲和力。确定对结合重要的特征包括 N4 哌嗪氮原子（但不是 N1 哌嗪氮）和喹啉基。喹嗪的喹啉氮原子也有助于亲和力，其被碳取代会使亲和力降低 20 倍。整个喹啉核对于结合不是必需的，某些单环芳基哌嗪，特别是那些在哌嗪环位置间位有氯基的单环芳基哌嗪（例如 mCPP、MK-212），也可以在 5-HT3 位点结合；然而，这些药物的亲和力至少比喹嗪本身低一个数量级。利用叔胺在5-HT1B位点的耐受性较差，而N-甲基取代基对5-HT3结合影响不大的事实，我们设计并合成了喹帕嗪的叔胺类似物，即N-甲基喹帕嗪（NMQ）。 NMQ 与 5-HT3 位点结合，亲和力与喹嗪类似；然而，与奎帕嗪不同，NMQ 对中心 5-HT1B 位点的亲和力非常小 (IC50 > 10000 nM)。
The binding affinities of a series of arylpiperazine derivatives at [3H]quipazine-labeled central 5-HT3 sites were investigated. Features determined to be important for binding include the N4 piperazine nitrogen atom (but not the N1 piperazine nitrogen), and quinolinyl group. The quinoline nitrogen atom of quipazine also contributes to affinity and its replacement by carbon reduces affinity by 20-fold. The entire quinoline nucleus is not necessary for binding, and certain monocyclic arylpiperazines, particularly those with a chloro group meta to the position of the piperazine ring (e.g. mCPP, MK-212), also bind at 5-HT3, sites; however, the affinities of these agents are at least an order of magnitude less that that of quipazine itself. Taking advantage of the fact that the tertiary amines are not well tolerated at 5-HT1B sites, but that N-methyl substituents have little effect on 5-HT3 binding, we designed and synthesized a tertiary amine analog of quipazine, i.e., N-methylquipazine (NMQ). NMQ binds at 5-HT3 sites with an affinity similar to that of quipazine; however, unlike quipazine, NMQ shows very little affinity (IC50 > 10000 nM) for central 5-HT1B sites.