scholarly journals Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology and Target Identification of Thio-wurtzine, a Potent Inhibitor of the Opioid Receptors and the Voltage-Dependent Calcium Channels

2021 ◽  
Author(s):  
Stephanie Aguero ◽  
Simon Megy ◽  
Raphael Terreux ◽  
Mailys Fournier ◽  
Daria Kulagina ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Opioid Receptors ◽  
Mechanism Of Action ◽  
Pain Treatment ◽  
Target Identification ◽  
Animal Experiments ◽  
Complex Mechanism ◽  
Narcotic Analgesics ◽  
Voltage Dependent

The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling and molecular dynamics simula-tions to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action, by targeting the mu, kappa, delta and ORL1 opioid receptors, and the voltage-gated calcium channels as well.

Succinylcholine Metabolite Succinic Acid Alters Steady State Activation in Muscle Sodium Channels

2000 ◽  
Vol 92 (5) ◽  
pp. 1385-1391 ◽  
Author(s):  
Gertrud Haeseler ◽  
Jacqueline Petzold ◽  
Hartmut Hecker ◽  
Axel Würz ◽  
Reinhard Dengler ◽  
...  
Keyword(s):  
Steady State ◽  
Succinic Acid ◽  
Sodium Channels ◽  
Animal Experiments ◽  
Cell Voltage ◽  
Hek293 Cells ◽  
Muscle Rigidity ◽  
Voltage Dependent

Background Animal experiments revealed that succinylcholine produced masseter muscle rigidity and activated myotonic discharges despite neuromuscular blockade with a nondepolarizing blocker. These results suggest that either succinylcholine or its metabolites might interfere directly with voltage-operated ion channels of the sarcolemma. The aim of this study was to examine effects of one product of succinylcholine hydrolysis, succinic acid, on voltage-gated muscle sodium (Na+) channels. Methods Alpha subunits of human muscle sodium channels were heterologously expressed in HEK293 cells. Activation of Na+ currents was examined applying standard whole-cell voltage-clamp protocols in the absence (control and washout) and presence of succinic acid in different concentrations (0.05-10 mm). Results Succinic acid shifted the midpoints of steady state activation plots in the direction of more negative test potentials, indicating that channels open during smaller depolarizations in the presence of the drug. The maximum amount of the negative shift in 10 mm succinic acid was -6.3 +/- 1.7 mV; the EC50 for this effect was 0.39 mm. In addition, succinic acid (10 mm) significantly enhanced maximum currents after depolarizations with respect to a series of control experiments. Conclusion Succinic acid facilitates voltage-dependent activation in muscle sodium channels in vitro. This might lead to muscle hyperexcitability in vivo.

scholarly journals Experimental Studies with Methylhydrazine Derivatives

1968 ◽  
Vol 17 (1) ◽  
pp. 158-170
Author(s):  
W. Bollag
Keyword(s):  
Mechanism Of Action ◽  
Fibrous Tissue ◽  
Animal Experiments ◽  
Experimental Studies ◽  
Cytotoxic Agents ◽  
Cross Resistance ◽  
Neoplastic Tissue ◽  
Walker Carcinoma

SummaryNatulan (Procarbazine) is a methylhydrazine derivative which in animal experiments inhibits a series of transplantable tumours. The Walker carcinoma is markedly affected. Even well established Walker tumours disappear completely under Natulan treatment. Tumour tissue is replaced by fibrous tissue. Natulan does not act selectively on neoplastic tissue, it also depresses the growth of other rapidly proliferating tissues such as the bone marrow.As regards the mechanism of action the following data are known: Natulan lowers the mitotic index by prolonging the interphase and hindering the cell from entering into mitosis. In Ehrlich ascites tumour cells chromatid breaks were observed. Natulan depolymerizes deoxyribonucleic acid (DNA) in vitro. In vivo the synthesis of DNA is inhibited. Furthermore alkylation of purine bases has been demonstrated. All these mechanisms may be responsible for the cytotoxic effect of methylhydrazine derivatives. Natulan does not possess cross-resistance towards other cytotoxic agents. This phenomenon is a further proof of its particular mechanism of action.

Calcium entry and mobilization signaling pathways in ANG II-induced renal vasoconstriction in vivo

1996 ◽  
Vol 270 (3) ◽  
pp. F398-F405 ◽  
Author(s):  
X. Ruan ◽  
W. J. Arendshorst
Keyword(s):  
Calcium Channels ◽  
Signaling Pathways ◽  
Calcium Mobilization ◽  
Bay K 8644 ◽  
Ang Ii ◽  
Renal Vasoconstriction ◽  
Intracellular Calcium Mobilization ◽  
Voltage Dependent ◽  
Dependent Inhibition

The purpose of this study was to determine the relative importance of calcium signaling pathways in angiotensin II (ANG II)-induced renal vasoconstriction in vivo. Nifedipine was used to antagonize dihydropyridine-sensitive voltage-dependent calcium channels; BAY K 8644 was employed to activate these calcium channels. Intracellular calcium mobilization was evaluated using TMB-8 or heparin to inhibit calcium release from sarcoplasmic reticulum. Renal blood flow was measured by electromagnetic flowmetry in anesthetized euvolemic Wistar-Kyoto rats. The animals were pretreated with indomethacin to avoid interactions with prostaglandins. ANG II (2 ng) or BAY K 8644 (1 microgram) was injected into the renal artery to produce a transient 30–50% decrease in renal blood flow without affecting arterial pressure. Coadministration of nifedipine with BAY K 8644 produced dose-dependent inhibition of the maximum renal vasoconstriction elicited by BAY K 8644. The calcium-channel antagonist had similar effects on ANG II-induced renal vasoconstriction. Nifedipine exerted maximum inhibition by blocking 50% of the peak ANG II response. To evaluate intracellular calcium mobilization, TMB-8 or heparin was coadministered with ANG II. Each agent produced dose-dependent inhibition of up to 50% of the maximum renal vasoconstriction produced by ANG II. The inhibitory effects of nifedipine and TMB-8 were additive; neither agent had an effect when ANG II AT1 receptors were antagonized with losartan. These observations indicate that one-half of the ANG II-induced constriction of renal resistance vessels is mediated by voltage-dependent L-type calcium channels responsive to the dihydropyridine nifedipine. The remaining 50% of the renal vasoconstriction elicited by ANG II is mediated by inositol 1,4,5-trisphosphate-mediated calcium mobilization from intracellular sources. The additive nature of the inhibitory effects indicates distinct mechanisms involving calcium mobilization and calcium entry signaling pathways that are of equal importance in ANG II activation of AT1 receptors to trigger constriction of renal resistance vessels under basal conditions

scholarly journals Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

2015 ◽  
Vol 112 (44) ◽  
pp. 13705-13710 ◽  
Author(s):  
Iulia Blesneac ◽  
Jean Chemin ◽  
Isabelle Bidaud ◽  
Sylvaine Huc-Brandt ◽  
Franck Vandermoere ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Low Voltage ◽  
Absence Epilepsy ◽  
Mammalian Brain ◽  
Systematic Analysis ◽  
Dynamic Regulation ◽  
Major Mechanism ◽  
Voltage Dependent

Phosphorylation is a major mechanism regulating the activity of ion channels that remains poorly understood with respect to T-type calcium channels (Cav3). These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has been linked to several neurological disorders, including absence epilepsy and neuropathic pain. Recent studies have revealed that T-type channels are modulated by a variety of serine/threonine protein kinase pathways, which indicates the need for a systematic analysis of T-type channel phosphorylation. Here, we immunopurified Cav3.2 channels from rat brain, and we used high-resolution MS to construct the first, to our knowledge, in vivo phosphorylation map of a voltage-gated calcium channel in a mammalian brain. We identified as many as 34 phosphorylation sites, and we show that the vast majority of these sites are also phosphorylated on the human Cav3.2 expressed in HEK293T cells. In patch-clamp studies, treatment of the channel with alkaline phosphatase as well as analysis of dephosphomimetic mutants revealed that phosphorylation regulates important functional properties of Cav3.2 channels, including voltage-dependent activation and inactivation and kinetics. We also identified that the phosphorylation of a locus situated in the loop I-II S442/S445/T446 is crucial for this regulation. Our data show that Cav3.2 channels are highly phosphorylated in the mammalian brain and establish phosphorylation as an important mechanism involved in the dynamic regulation of Cav3.2 channel gating properties.

scholarly journals IFITM3 influences the invasion and metastasis of hepatocellular carcinoma by regulating NCAPG through phosphorylation

2020 ◽  
Author(s):  
Weiwei Liu ◽  
Rongguiyi Zhang ◽  
Enliang Li ◽  
Jiakun Wang ◽  
Linquan Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mechanism Of Action ◽  
Bioinformatics Analysis ◽  
Animal Experiments ◽  
Scratch Test ◽  
Hepatobiliary Surgery ◽  
Invasion And Metastasis ◽  
Liver Hepatocellular Carcinoma ◽  
The Relationship

Abstract Background:Several studies have demonstrated that the expressions of IFITM3 and NCAPG are closely related to the prognosis of various tumors. However, the mechanism of action of these two is not yet clear. In this study, we have explored the mechanism of action of IFITM3 and NCAPG in the promotion of the invasion and metastasis of hepatocellular carcinoma (HCC). Methods: Specimens of liver cancer and adjacent tissues from 55 HCC patients at the Department of Hepatobiliary Surgery, Second Affiliated Hospital of Nanchang University were collected, and the expressions of NCAPG and IFITM3 were determined by qRT-PCR and Western blotting. Through the analysis of multiple databases, the relationship between IFITM3 and NCAPG was established by the CO-IP method. SiRNA and plasmids were used to downregulate and upregulate IFITM3, and the expression of STAT3/CDK1, NCAPG mRNA, and protein was observed. After downregulating and upregulating the expression of IFITM3 and NCAPG, the ability of HCC cells to invade and metastasize was determined using a scratch test and Transwell assays. After using pathway inhibitors and activators, the expression of NCAPG was observed.Results: According to the database, both IFITM3 and NCAPG were highly expressed in liver hepatocellular carcinoma. We also confirmed that IFITM3 and NCAPG were upregulated in HCC tissues and cells. Furthermore, the bioinformatics analysis and CO-IP indicated that there was a protein interaction between IFITM3 and NCAPG, and that IFITM3 could regulate NCAPG by phosphorylating it. We further confirmed our observations by retrospective experiments. The reuse of pathway inhibitors and activators indicated that IFITM3 could regulate NCAPG through STAT3/CDK1 to promote the invasion and metastasis of HCC. Finally, the animal experiments confirmed that the results were also reproducible in vivo. Conclusion: IFITM3 can regulate NCAPG through STAT3/CDK1 to promote the invasion and metastasis of HCC.

scholarly journals The effects and possible mechanism of action of apolipoprotein M on the growth of breast cancer cells

2021 ◽  
Author(s):  
Ying Zhou ◽  
Shuang Yao ◽  
Miaomei Yu ◽  
Jiang Wei ◽  
Qi Fang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mechanism Of Action ◽  
Breast Cancer Cells ◽  
Animal Experiments ◽  
Breast Cancer Cell Lines ◽  
Apolipoprotein M ◽  
Main Pathway ◽  
The Difference ◽  
Mcf 7

Abstract Background: To investigate the effects and mechanism of action of apolipoprotein M (ApoM) on the growth of breast cancer (BC) cells.Methods and Results: Bioinformatics, cell experiments and animal experiments were used to verify the effect of ApoM on breast cancer cell lines and breast tumor growth in vivo. ApoM expression was significantly reduced in BC tissues, and patients with lower ApoM mRNA expression had a poorer prognosis (P<0.0001). Besides, ApoM can partially inhibit the proliferative, migratory and invasive processes of BC cells. In vivo, the difference between ApoM-OE and NC groups was no significant. The level of vitamin D receptor (VDR) protein in MDA-MB-231 cells was increased by overexpression of ApoM (P<0.05), while in MCF-7 cells, VDR levels decreased (P<0.05).Conclusions: ApoM can partially inhibit the growth of BC cells. VDR may play a role, but is not the main pathway.

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