氯苯氧基衍生物——组胺H3受体配体的胆碱酯酶抑制活性。
Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands.
作者信息
Łażewska Dorota, Jończyk Jakub, Bajda Marek, Szałaj Natalia, Więckowska Anna, Panek Dawid, Moore Caitlin, Kuder Kamil, Malawska Barbara, Kieć-Kononowicz Katarzyna
机构信息
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
出版信息
Bioorg Med Chem Lett. 2016 Aug 15;26(16):4140-5. doi: 10.1016/j.bmcl.2016.04.054. Epub 2016 Apr 20.
In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.
近年来，多靶点导向配体已成为寻找阿尔茨海默病新治疗方法的一种有趣策略。将组胺H3受体拮抗剂/反向激动剂和胆碱酯酶抑制剂结合在一个分子中可能会提供新的治疗机会。在此，我们展示了组胺H3受体配体——氯苯氧基烷基胺衍生物针对胆碱酯酶（乙酰胆碱酯酶和丁酰胆碱酯酶）的生物学评价。目标化合物在低微摩尔范围内显示出胆碱酯酶抑制活性。该组中最有效的是1-(7-(4-氯苯氧基)庚基)高哌啶（18），对两种酶均有抑制作用（人源乙酰胆碱酯酶IC50 = 1.93μM 和电鳗丁酰胆碱酯酶IC50 = 1.64μM）。进行了分子模拟研究以解释18与组胺H3受体以及胆碱酯酶的结合模式。
Zotero 插件