A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT6 receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HT6R as the main target, and for the 5-HT1AR, 5-HT7R and D2R as competitive ones, were determined in the radioligand binding assays. Docking to the 5-HT6R homology model was performed to support SAR analysis. Results showed that the branching of the methoxyl linker increased affinity for the human 5-HT6R whereas an unsaturated bond within the linker dramatically reduced desirable activity. Both experimental and theoretical studies confirmed the previously postulated beneficial role of the aromatic size for interaction with the 5-HT6R. Thus, the largest naphthyl moiety yielded the highest activity. In particular, 4-(4-methylpiperazin-1-yl)-6-(1-(naphthalen-1-yloxy)ethyl)-1,3,5-triazin-2-amine (24), the most potent 5-HT6R agent found (Ki = 23 nM), can be a new lead structure for further search and development.

中文翻译：

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合成和计算机辅助分析了取代的1,3,5-三嗪基哌嗪中5-HT6血清素受体新配体的接头作用。

基于先前公开的2-氨基-4-苄基-（4-甲基哌嗪-1-基）-设计了一系列2-氨基-4-（4-甲基哌嗪-1-基）-1,3,5-三嗪。 1,3,5-三嗪，以评估三嗪部分与芳香族取代基之间的连接基团对人5-羟色胺5-HT6受体亲和力的作用。作为新的连接基，引入了两个碳原子（乙基或乙烯基）或氧基烷基链（甲氧基，2-乙氧基，2-丙氧基）。在放射性配体结合测定中确定了化合物对5-HT6R作为主要靶标以及对5-HT1AR，5-HT7R和D2R作为竞争化合物的亲和力。对接至5-HT6R同源性模型以支持SAR分析。结果表明，甲氧基连接基的分支增加了对人5-HT6R的亲和力，而连接基内的不饱和键则大大降低了所需的活性。实验和理论研究均证实了先前推测的芳香族分子大小对与5-HT6R相互作用的有益作用。因此，最大的萘基部分产生最高的活性。特别是最有效的5--4-（4-甲基哌嗪-1-基）-6-（1-（萘-1-基氧基）乙基）-1,3,5-三嗪-2-胺（24）发现HT6R试剂（Ki = 23 nM），可以作为进一步寻找和开发的新的潜在客户结构。