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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
2023; Wiley; Volume: 38; Issue: 2 Linguagem: Inglês
10.1111/fcp.12960
ISSN1472-8206
AutoresLarissa Santos Oliveira, Maria Kueirislene Amâncio Ferreira, Francisco Wagner Queiroz Almeida-Neto, Antônio 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,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoAbstract 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‐HTR 1 , 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 2A R 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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