Kuder Kamil J, Kotańska Magdalena, Szczepańska Katarzyna, Mika Kamil, Reiner-Link David, Stark Holger, Kieć-Kononowicz Katarzyna
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, Poland.
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, Poland.
Molecules. 2021 Apr 15;26(8):2300. doi: 10.3390/molecules26082300.
In an attempt to find new dual acting histamine H receptor (HR) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H receptor (hHR) ligand KSK63. As a result, 15 obtained compounds show moderate hHR affinity, the best being the compound (hHR = 518 nM). Docking to the histamine HR homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound (hHR = 592 nM) showed the strongest antioxidant properties at the concentration of 10 mol/L. It significantly reduced the amount of free radicals presenting 50-60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hHR affinity, (QD13) constitutes a starting point for the search of potential dual acting HR ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.
为了寻找新型双效组胺H受体（HR）配体，我们基于本研究小组之前描述的高活性和选择性人组胺H受体（hHR）配体KSK63，设计了一系列化合物。结果，获得的15种化合物表现出中等的hHR亲和力，其中最佳的是化合物（hHR = 518 nM）。与组胺HR同源模型对接揭示了两种可能的结合模式，两种情况下关键相互作用均得以保留。为了寻找可能的双效配体，对所选化合物进行了抗氧化性能测试。化合物（hHR = 592 nM）在10 μmol/L浓度下表现出最强的抗氧化性能。在2,2-二苯基-1-苦基肼（DPPH）测定中，它显著降低了自由基的量，呈现出50 - 60%的抗坏血酸活性，并且在铁还原抗氧化能力（FRAP）测定中也表现出抗氧化性能。尽管抗氧化机制尚不清楚且hHR亲和力中等，但（QD13）构成了寻找潜在双效HR配体的起点——这是治疗与神经元氧化应激增加相关的神经疾病的有前景的工具。
