设计，合成和分子模拟的新的庞大的Fananserin衍生物具有潜在的抗抑郁药的药理作用。,Bioorganic & Medicinal Chemistry

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设计，合成和分子模拟的新的庞大的Fananserin衍生物具有潜在的抗抑郁药的药理作用。
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-06-21 , DOI: 10.1016/j.bmc.2019.06.028
Przemysław Zaręba ₁ , Jolanta Jaśkowska ₁ , Izabela Czekaj ₁ , Grzegorz Satała ₂

Affiliation

现在已知许多神经递质系统负责中枢神经系统（CNS）的疾病。中枢神经系统最常见的疾病之一是抑郁症。考虑到在抑郁症的治疗和起源中，最重要的是5-HT1A，5-HT2A，5-HT6和5-HT7组以及多巴胺D2R的5-羟色胺受体受体。在寻找可能有用的化合物时，我们决定从著名的Fananserin的结构开始。我们尝试开发新的衍生物，与Fananserin相比活性有所变化。文献分析和虚拟筛选涌现出具有己基碳链的1,8萘甲磺胺/内酰胺的卤化长链芳基哌嗪衍生物的合成基团。通过微波辅助合成开发了化合物的获得方法。反应在乙腈，水或无溶剂条件下进行。测试获得的化合物对上述5-羟色胺受体的亲和力。该工作设法获得了对选定的5-羟色胺受体起作用的化合物，包括多功能5-HT1A / 5-HT7 / D2配体5k，双5-HT1A / D2配体5j和选择性5-HT1A配体5r和5c。SAR分析显示，配体结构对5-HT6受体的亲和力具有明显的依赖性。使用分子对接方法讨论了这种关系。还对选定的配体进行了保形分析，并使用DFT（理论的B3LYP / 6-311 + G（d，p）水平）方法计算了Fukui指数。使用分子对接方法进行的研究和分析，可以为属于上述组的5-羟色胺受体的新配体的设计选择更多的结构修饰途径。此外，进行的研究表明，使用Fukui指数预测新分子的生物学活性的潜力。

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Design, synthesis and molecular modelling of new bulky Fananserin derivatives with altered pharmacological profile as potential antidepressants.

It is now known that many neurotransmitter systems are responsible for diseases of the central nervous system (CNS). One of the most common CNS disease is depression. Considering that in the treatment and the genesis of depression, the most important are the serotonin receptors from 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 groups, and dopamine D2R this article describes searching for group of new ligands for mentioned receptors. In the searching for potentially useful compound, we decided to start from the structure of well-known Fananserin. We tried to developed new derivatives, with changed profile of activity compared to Fananserin. Literature analysis and virtual screening emerged group of halogenated long-chain arylpiperazines derivatives of 1,8 naphthosultam/lactam with hexyl carbon chain to synthesis. The compounds obtaining method was developed with a microwave assisted synthesis. Reactions were carried out in acetonitrile, water or in solvent-free conditions. The obtained compounds were tested for their affinity for the serotonin receptors mentioned above. The work managed to obtain compounds acting on selected serotonin receptors, including multifunctional 5-HT1A/5-HT7/D2 ligand 5k, dual 5-HT1A/D2 ligand 5j and selective 5-HT1A ligands 5r and 5c. The SAR analysis showed a visible dependence of affinity for the 5-HT6 receptors from structure of ligands. This relationship was discussed using molecular docking methods. A conformal analysis was also performed for selected ligands and the Fukui indexes were calculated using the DFT (B3LYP/6-311+G (d,p) level of theory) methods. The conducted research and analysis using molecular docking methods allows for selecting further pathways of structural modifications in the design of new ligands for serotonin receptors belonging to the group mentioned. What is more, conducted research show the potential using of Fukui indices to predict the biological activity of new molecules.

更新日期：2019-06-21

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