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

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY Fundamental & Clinical Pharmacology Pub Date : 2023-10-16 DOI:10.1111/fcp.12960

Larissa Santos Oliveira, Maria Kueirislene Amâncio Ferreira, Francisco Wagner de Queiroz Almeida-Neto, Antonio Wlisses da Silva, José Ivo Lima Pinto Filho, Matheus Nunes da Rocha, Emanuelle Machado Marinho, Walber Henrique Ferreira Ribeiro, Márcia Machado Marinho, Emmanuel Silva Marinho, Jane Eire Silva Alencar de Menezes, Hélcio Silva dos Santos

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Abstract

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_A 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-HTR₁, 5-HTR_2A/2C, and 5-HTR_3A/3B 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_2A and 5-HTR_3A/3B receptors. The interaction of C2OHPDA with 5-HT_2AR and 5-HT_3A 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.

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合成查尔酮（E）-3-（4-（二甲基氨基）苯基）-1-（2-羟基苯基）丙-2-烯-1-酮的合成、分子对接、ADMET和对成年斑马鱼抗焦虑作用的评估：体内和计算机方法。

背景：焦虑症表现为生物、心理、气质和环境因素之间的复杂相互作用；可用于治疗焦虑症的药物，如苯二氮卓类药物（BZDs），会产生一些不必要的副作用。尽管有有用的治疗方法，但仍需要比BZD更有效、安全性更好的抗焦虑药物。查尔酮或1,3-二苯基-2-丙烯-1-酮可以是一种替代品，因为这类化合物主要由于与GABAA受体和5-羟色胺能系统的相互作用而显示出治疗潜力。目的：本研究评价查尔酮（E）-3-（4-（二甲基氨基）苯基）-1-（2-羟基苯基）丙-2-烯-1-酮（C2OHPDA）对成年斑马鱼（Danio rerio）（ZFa）的抗焦虑作用 = 6/组）腹膜内治疗（i.p.；20 μL）与查尔酮（4、20和40 mg/kg）和载体（DMSO 3%；20 μL），进行运动活性和96小时急性毒性试验。还进行了光/暗测试，并通过5-HTR1、5-HTR2A/2C和5-HTR3A/3B受体的拮抗剂评估5-羟色胺能机制（5-HT）。研究了查尔酮的位置及其受体的优先取向的预测，以及给药后该过程中涉及的药代动力学参数（ADMET）。结果：C2OHPDA无毒性，能降低ZFa的运动活性。此外，查尔酮对中枢神经系统（CNS）表现出抗焦虑作用，由5-羟色胺能系统介导，对5-HT2A和5-HTR3A/3B受体起作用。分子对接研究证实了C2OHPDA与5-HT2A受体和5-HT3A受体的相互作用，观察到的亲和能分别为-8.7和-9.1 kcal/mol。结论：因此，这项研究增加了新的证据，并强调查尔酮有可能用于开发具有抗焦虑特性的化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.