合成、分子对接、ADMET 分析以及(E)-3-(4-(二甲氨基)苯基)-1-(2-羟基苯基)丙-2-烯-1-酮类合成查尔酮在成年斑马鱼中的抗焦虑作用评估：体内和计算方法。
Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one: An in vivo and in silico approach.
机构信息
Science and Technology, Graduate Program in Natural Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
Northeast Biotechnology Network, Graduate Program of Biotechnology, State University of Ceará, Fortaleza, Ceará, Brazil.
出版信息
Fundam Clin Pharmacol. 2024 Apr;38(2):290-306. doi: 10.1111/fcp.12960. Epub 2023 Oct 16.
BACKGROUND
Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABA receptors and serotonergic system.
OBJECTIVES
This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa).
METHODS
Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 μL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 μL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR , 5-HTR , and 5-HTR receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration.
RESULTS
As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT and 5-HTR receptors. The interaction of C2OHPDA with 5-HT R and 5-HT receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1 kcal/mol, respectively.
CONCLUSION
Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.
背景
焦虑症是生物、心理、气质和环境因素复杂相互作用的结果；用于治疗焦虑症的药物，如苯二氮䓬类（BZDs），存在多种不良反应。尽管有一些有效的治疗方法，但仍需要更有效的抗焦虑药物，其安全性要优于 BZDs。查尔酮或 1,3-二苯基-2-丙烯-1-酮类化合物可能是一种替代方法，因为该类化合物主要通过与 GABA 受体和 5-羟色胺能系统相互作用显示出治疗潜力。
目的
本研究评估查尔酮（E）-3-（4-（二甲基氨基）苯基）-1-（2-羟基苯基）-2-丙烯-1-酮（C2OHPDA）在成年斑马鱼（Danio rerio）（ZFa）中的抗焦虑作用。
方法
每组动物（n=6/组）通过腹腔内（i.p.；20 μL）给予查尔酮（4、20 和 40 mg/kg）和载体（DMSO 3%；20 μL），然后进行运动活性测试和 96 小时急性毒性测试。还进行了明暗测试，通过 5-HT1A、5-HT2A 和 5-HT2C 受体拮抗剂评估 5-羟色胺能机制。研究了查尔酮与受体的位置和优先取向的预测，以及给药后涉及的药代动力学参数（ADMET）。
结果
结果表明，C2OHPDA 没有毒性，可减少 ZFa 的运动活性。此外，查尔酮对中枢神经系统（CNS）具有抗焦虑作用，其作用机制涉及 5-羟色胺能系统，对 5-HT 和 5-HT1A 受体有作用。分子对接研究证实了 C2OHPDA 与 5-HT1A 和 5-HT2A 受体的相互作用，观察到的亲和力能分别为-8.7 和-9.1 kcal/mol。
结论
因此，本研究提供了新的证据，并强调了查尔酮可能可用于开发具有抗焦虑特性的化合物。
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