Synthesis and antidepressant effect of novel aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7

Gu, Zheng-Song; Wang, Wen-Tao; Qian, Hao; Zhou, Ainan; Sun, Hongbin; Zhang, Qingwei; Li, Jianqi

doi:10.1016/j.bmcl.2019.126703

Cited by 21 publications

(9 citation statements)

References 14 publications

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“…This suggests that to exert an antidepressant-like effect, HBK-10 requires the availability of serotonin in the synaptic cleft. As expected, the results are in agreement with our previous studies on 2-metoxyphenypiperazine derivatives [ 19 , 20 , 21 ], as well as studies of other researchers [ 44 , 45 , 46 , 47 , 48 ].…”

Section: Discussionsupporting

confidence: 93%

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

et al. 2021

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The increasing number of patients reporting depressive symptoms requires the design of new antidepressants with higher efficacy and limited side effects. As our previous research showed, 2-methoxyphenylpiperazine derivatives are promising candidates to fulfill these criteria. In this study, we aimed to synthesize a novel 2-methoxyphenylpiperazine derivative, HBK-10, and investigate its in vitro and in vivo pharmacological profile. After assessing the affinity for serotonergic and dopaminergic receptors, and serotonin transporter, we determined intrinsic activity of the compound at the 5-HT1A and D2 receptors. Next, we performed behavioral experiments (forced swim test, tail suspension test) to evaluate the antidepressant-like activity of HBK-10 in naïve and corticosterone-treated mice. We also assessed the safety profile of the compound. We showed that HBK-10 bound strongly to 5-HT1A and D2 receptors and presented antagonistic properties at these receptors in the functional assays. HBK-10 displayed the antidepressant-like effect not only in naïve animals, but also in the corticosterone-induced mouse depression model, i.e., chronic administration of HBK-10 reversed corticosterone-induced changes in behavior. Moreover, the compound’s sedative effect was observed at around 26-fold higher doses than the antidepressant-like ones. Our study showed that HBK-10 displayed a favorable pharmacological profile and may represent an attractive putative treatment candidate for depression.

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Section: Discussionsupporting

confidence: 93%

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

et al. 2021

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“…Twenty-five studies that used compounds nonspecific to the 5-HT7 receptor identified potential antidepressant effects depression such as immobility time, in both the FST or TST ( Abbas et al, 2009 ; Cates et al, 2013 ; Chlon-Rzepa et al, 2013 ; Gu et al, 2019 , 2018 , 2017 ; Guilloux et al, 2013 ; Jankowska et al, 2020 ; Kim et al, 2014 ; Kołaczkowski et al, 2014 ; Latacz et al, 2018 ; Li et al, 2013 ; Mørk et al, 2012 ; Partyka et al, 2017 , 2019 ; Pytka et al, 2015 , 2017a , 2017b , 2018 ; Wang et al, 2019 ; Waszkielewicz et al, 2015 ; Wróbel et al, 2019 ; Zagórska et al, 2015 , 2016 ; Zajdel et al, 2013 ).…”

Section: Preclinical Study Resultsmentioning

confidence: 99%

The 5-HT7 receptor system as a treatment target for mood and anxiety disorders: A systematic review

Gottlieb,

Li,

Young

et al. 2023

J Psychopharmacol

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Background: Preclinical animal and preliminary human studies indicate that 5-HT7 antagonists have the potential as a new treatment approach for mood and anxiety disorders. In this systematic review, we aimed to review the relationship between the 5-HT7 receptor system and mood and anxiety disorders, and to explore the pharmacology and therapeutic potential of medications that target the 5-HT7 receptor for their treatment. Methods: Medline, Cochrane Library, EMBASE, PsycINFO databases, the National Institute of Health website Clinicaltrials.gov, controlled-trials.com, and relevant grey literature were used to search for original research articles, and reference lists of included articles were then hand searched. Results: Sixty-four studies were included in the review: 52 animal studies and 12 human studies. Studies used a variety of preclinical paradigms and questionnaires to assess change in mood, and few studies examined sleep or cognition. Forty-four out of 47 (44/47) preclinical 5-HT7 modulation studies identified potential antidepressant effects and 20/23 studies identified potential anxiolytic effects. In clinical studies, 5/7 identified potential antidepressant effects in major depressive disorder, 1/2 identified potential anxiolytic effects in generalized anxiety disorder, and 3/3 identified potential antidepressant effects in bipolar disorders. Conclusion: While there is some evidence that the 5-HT7 receptor system may be a potential target for treating mood and anxiety disorders, many agents included in the review also bind to other receptors. Further research is needed using drugs that bind specifically to 5-HT7 receptors to examine treatment proof of concept further.

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“…The range of pKi values for the presented drugs was within 5.57–9.70 (median = 7.54). The listed examples of drugs can be found in our curated database of 5-HT1A [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

Section: Resultsmentioning

confidence: 99%

Curated Database and Preliminary AutoML QSAR Model for 5-HT1A Receptor

et al. 2021

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Introduction of a new drug to the market is a challenging and resource-consuming process. Predictive models developed with the use of artificial intelligence could be the solution to the growing need for an efficient tool which brings practical and knowledge benefits, but requires a large amount of high-quality data. The aim of our project was to develop quantitative structure–activity relationship (QSAR) model predicting serotonergic activity toward the 5-HT1A receptor on the basis of a created database. The dataset was obtained using ZINC and ChEMBL databases. It contained 9440 unique compounds, yielding the largest available database of 5-HT1A ligands with specified pKi value to date. Furthermore, the predictive model was developed using automated machine learning (AutoML) methods. According to the 10-fold cross-validation (10-CV) testing procedure, the root-mean-squared error (RMSE) was 0.5437, and the coefficient of determination (R2) was 0.74. Moreover, the Shapley Additive Explanations method (SHAP) was applied to assess a more in-depth understanding of the influence of variables on the model’s predictions. According to to the problem definition, the developed model can efficiently predict the affinity value for new molecules toward the 5-HT1A receptor on the basis of their structure encoded in the form of molecular descriptors. Usage of this model in screening processes can significantly improve the process of discovery of new drugs in the field of mental diseases and anticancer therapy.

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Synthesis and antidepressant effect of novel aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7

Cited by 21 publications

References 14 publications

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

The 5-HT7 receptor system as a treatment target for mood and anxiety disorders: A systematic review

Curated Database and Preliminary AutoML QSAR Model for 5-HT1A Receptor

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