In the light of recent lines of evidence, 5-HT₆R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT₆R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT₆R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K_i < 100 nM) and selectivity towards 5-HT₆R, with respect to 5-HT_2AR, 5-HT₇R and D₂R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT₆R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K_i = 6 nM), very strong 5-HT₆R antagonistic action (K_B = 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research.

根据最近的证据，5-HT ₆ R配体是未来治疗记忆障碍的有前途的工具。因此，本研究提供了具有认知作用的强效5-HT ₆ R药物，它代表了1,3,5-三嗪的原始化学类别，与广泛研究的砜和吲哚样5-HT ₆ R配体不同。新化合物经过合理设计，是对铅4-（1-（2-氯苯氧基）乙基）-6-（4-甲基哌嗪-1-基）-1,3,5-三嗪-2-胺的修饰（1） ，涉及引入：（i）苯环上的两个氯和（ii）将三嗪环连接到芳族醚上的各种连接基。合成，体外和对19种新化合物进行了体内生物学测试和计算机辅助SAR分析。相对于5-HT _2A R，5-HT ₇ R和D ₂ R，大多数新的三嗪类 化合物对5-HT ₆ R表现出高亲和力（K _i <100 nM）和选择性。晶体学支持的对接研究包括量子极化的配体对接（QPLD），表明氯原子可能参与不同类型的卤素键，但是，连接子的性质似乎主要影响5-HT ₆ R的亲和力。4- [1-（2,5-二氯苯氧基）丙基] -6-（4-甲基哌嗪-1-基）-1,3,5-三嗪-2-胺（9），显示：最高亲和力（K_i  = 6 nM），非常强的5-HT ₆ R拮抗作用（ K _B  = 27 pM），在大鼠的新对象识别（NOR）测试中的体内认知作用，在PAMPA模型中具有很好的渗透性并满足体外安全性，被确定为迄今为止最有效的1,3,5-三嗪试剂，可用作进一步研究的新线索。