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Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3\u2010diphenyl\u20102\u2010proper\u20101\u2010ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABA<jats:sub>A<\/jats:sub> receptors and serotonergic system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This study evaluated the anxiolytic potential of chalcone (<jats:italic>E<\/jats:italic>)\u20103\u2010(4\u2010(dimethylamino)phenyl)\u20101\u2010(2\u2010hydroxyphenyl)prop\u20102\u2010en\u20101\u2010one (C2OHPDA) in adult zebrafish (<jats:styled-content style=\"fixed-case\"><jats:italic>Danio rerio<\/jats:italic><\/jats:styled-content>) (ZFa).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Each animal (<jats:italic>n<\/jats:italic>\u2009=\u20096\/group) was treated intraperitoneally (i.p.; 20\u2009\u03bcL) with the chalcone (4, 20, and 40\u2009mg\/kg) and with the vehicle (DMSO 3%; 20\u2009\u03bcL), being submitted to the tests of locomotor activity and 96\u2010h acute toxicity. The light\/dark test was also performed, and the serotonergic mechanism (5\u2010HT) was evaluated through the antagonists of the 5\u2010HTR<jats:sub>1<\/jats:sub>, 5\u2010HTR<jats:sub>2A\/2C<\/jats:sub>, and 5\u2010HTR<jats:sub>3A\/3B<\/jats:sub> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2010HT<jats:sub>2A<\/jats:sub> and 5\u2010HTR<jats:sub>3A\/3B<\/jats:sub> receptors. The interaction of C2OHPDA with 5\u2010HT<jats:sub>2A<\/jats:sub>R and 5\u2010HT<jats:sub>3A<\/jats:sub> receptors was confirmed by molecular docking study, the affinity energy observed was \u22128.7 and \u22129.1\u00a0kcal\/mol, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.<\/jats:p><\/jats:sec>","DOI":"10.1111\/fcp.12960","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T04:00:36Z","timestamp":1697515236000},"page":"290-306","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone 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