Study on chemical modification and analgesic activity of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide

Nie, Cunbin; Li, Qifei; Qiao, Yunfei; Hu, Jing; Gao, Mengkang; Wang, Yusui; Qiao, Zhenrui; Wang, Qiang; Yang, Lin; Qian, Hai

doi:10.1016/j.ejmech.2020.112236

Cited by 12 publications

(2 citation statements)

References 23 publications

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“…By searching the small molecule database PubChem ( https://pubchem.ncbi.nlm.nih.gov/ ), TCMSP ( http://tcmspw.com/tcmsp.php ), TCMID ( http://www.Megabionet.org/tcmid/ ) and relevant literature, we found 60 components in CF ( Supplementary Table S1 ). And then, we searched for 10 TRPV1 agonists and 10 TRPV1 antagonists from the literature ( Supplementary Table S2 ) and downloaded small molecule ligands ( Gavva, 2008 ; Gunthorpe and Szallasi, 2008 ; Burgess and Williams, 2010 ; Li et al, 2011 ; Szolcsányi and Sándor, 2012 ; Sugimoto et al, 2013 ; Yin, 2019 ; Choi et al, 2020 ; Duarte et al, 2020 ; Mazeto et al, 2020 ; More et al, 2020 ; Nie, 2020 ). We also had to randomly download 90 compounds from the PubChem database that did not have well-defined TRPV1 agonist activity for later verification.…”

Section: Methodsmentioning

confidence: 99%

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Song,

Mi,

Zhao

et al. 2024

Front. Pharmacol.

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Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation.Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel.Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine.Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.

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Section: Methodsmentioning

confidence: 99%

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Song,

Mi,

Zhao

et al. 2024

Front. Pharmacol.

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“…However, the poor metabolic stability, aqueous solubility, and oral bioavailability limited its further development (Benko et al., 2012). Besides, the tendency of BCTC to induce hyperthermia side effect in preclinical models turned out to be a hurdle and led to its withdrawal from clinical development (Nie et al., 2020). Multiple strategies have been developed to improve the water solubility and pharmacokinetic characteristic of BCTC (Gao et al., 2019; Hu et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists

Jing,

Liu

2024

Chem Biol Drug Des

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Transient receptor potential vanilloid 1 (TRPV1) is a non‐selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L‐21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L‐21 exhibited low risk of hyperthermia side effect. These results indicated that L‐21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.

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Microwave‐Assisted One‐Pot Synthesis of Tetrahydro‐β‐Carbolines by Fe(II)‐Catalyst: Utilizing Methanol as Methylene Synthon

Khan,

Reddyrajula,

Sakla

et al. 2024

Asian J Org Chem

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The synthesis of tetrahydro‐β‐carbolines (THβCs) framework is a fundamental aspect of medicinal chemistry due to their significant pharmacological applications. Herein, we developed a microwave‐assisted novel approach for the synthesis of THβC scaffolds utilizing ferrous(II) chloride as an earth abundant metal catalyst and methanol used as valuable methylene source. This methodology demonstrates excellent functional group tolerance and provides N2‐substituted THβCs in good to excellent yields. Overall, this study highlights a sustainable and practical strategy for the synthesis of biologically important THβCs, thereby offering promising prospects in the drug discovery and development.

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Study on chemical modification and analgesic activity of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide

Cited by 12 publications

References 23 publications

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists

Microwave‐Assisted One‐Pot Synthesis of Tetrahydro‐β‐Carbolines by Fe(II)‐Catalyst: Utilizing Methanol as Methylene Synthon

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