Leonurine Explained

Leonurine (also known as SCM-198 in research) is a pseudoalkaloid that has been isolated from Leonotis leonurus, Leonotis nepetifolia, Leonurus japonicus, Leonurus cardiaca (motherwort), Leonurus sibiricus, as well as other plants of family Lamiaceae. Leonurine is easily extracted into water.[1]

Research

Leonurine weakly binds to multiple GABA receptor sites including the GABAA receptor.[2] [3] However, it shows much higher affinity as a 5-HT3A receptor antagonist.[4] 5-HT3A antagonists have been shown to help prevent nausea and vomiting as well as the negative effects of serotonin in the gastrointestinal tract.[5] [6]

Leonurine can regulate a variety of functions including oxidative stress, inflammation, fibrosis, apoptosis, and metabolic disorder.[7] [8] [9]

Leonurine has demonstrated antidepressant-like action and has been shown to increase levels of serotonin, noradrenaline, and dopamine in chronic mild stress studies on mice and inhibits the production of pro-inflammatory cytokines.[10] [11] [12]

Leonurine has been investigated as a potential treatment for cardiovascular disorders.[13] [14] [15] [16] It protects against oxidative damage from ischemic stroke and demonstrates neuroprotective activity against focal cerebral ischemia brain injury induced on rats.[17] [18] [19]

Leonurine protects mice from pneumonia induced by influenza A.[20]

Leonurine has demonstrated anti-cancer activity in vitro and in animal studies.[21] [22] [23] [24] [25]

Metabolites

Metabolites of leonurine in rats dosed orally include leonurine-10-O-sulfate (the sulfate conjugate of leonurine), leonurine-10-O-β-D-glucuronide (the glucuronide metabolite of leonurine) and an O-demethylated leonurine analog that has not yet had its structure definitively confirmed.[26]

Chemical synthesis

Leonurine can be synthesized starting from eudesmic acid. Reaction with sulfuric acid produces syringic acid. Protection with ethyl chloroformate followed by reaction with thionyl chloride (SOCl2) and then tetrahydrofuran yields 4-carboethoxysyringic acid 4-chloro-1-butyl ester. The chloride is then converted to an amino group via a Gabriel synthesis (with potassium phthalimide) followed by hydrazinolysis (Ing–Manske procedure). The final step is reaction of the amine with S-methylisothiourea hemisulfate salt.

Further reading

Notes and References

  1. Web site: The Leonurine and its preparation. 2008. An Hui New Star Pharmaceutical Development Co.. 2008-08-28. dead. https://web.archive.org/web/20080515223641/http://www.newstar-chem.com/english/display.asp?id=208. 2008-05-15.
  2. Çiçek SS . Structure-Dependent Activity of Natural GABA(A) Receptor Modulators . Molecules . 23 . 7 . 1512 . June 2018 . 29932138 . 6100244 . 10.3390/molecules23071512 . free .
  3. Rauwald HW, Savtschenko A, Merten A, Rusch C, Appel K, Kuchta K . GABAA Receptor Binding Assays of Standardized Leonurus cardiaca and Leonurus japonicus Extracts as Well as Their Isolated Constituents . Planta Medica . 81 . 12–13 . 1103–1110 . August 2015 . 26218338 . 10.1055/s-0033-1352395 .
  4. Hoffmann KM, Herbrechter R, Ziemba PM, Lepke P, Beltrán L, Hatt H, Werner M, Gisselmann G . 6 . Kampo Medicine: Evaluation of the Pharmacological Activity of 121 Herbal Drugs on GABAA and 5-HT3A Receptors . Frontiers in Pharmacology . 7 . 219 . 2016 . 27524967 . 4965468 . 10.3389/fphar.2016.00219 . free .
  5. Book: Theriot J, Wermuth HR, Ashurst JV . StatPearls . 2022 . StatPearls Publishing . Antiemetic Serotonin-5-HT3 Receptor Blockers . 30020690 .
  6. Web site: List of 5HT3 receptor antagonists (5hydroxytryptamine receptor antagonists) .
  7. Li YY, Lin YK, Liu XH, Wang L, Yu M, Li DJ, Zhu YZ, Du MR . 6 . Leonurine: From Gynecologic Medicine to Pleiotropic Agent . Chinese Journal of Integrative Medicine . 26 . 2 . 152–160 . February 2020 . 31069695 . 10.1007/s11655-019-3453-0 . 148571306 .
  8. Li N, Xu Q, Liu Q, Pan D, Jiang Y, Liu M, Liu M, Xu H, Lin C . 6 . Leonurine attenuates fibroblast-like synoviocyte-mediated synovial inflammation and joint destruction in rheumatoid arthritis . Rheumatology . 56 . 8 . 1417–1427 . August 2017 . 28431044 . 10.1093/rheumatology/kex142 . free .
  9. Zheng S, Zhuang T, Tang Y, Wu R, Xu T, Leng T, Wang Y, Lin Z, Ji M . 6 . Leonurine protects against ulcerative colitis by alleviating inflammation and modulating intestinal microflora in mouse models . Experimental and Therapeutic Medicine . 22 . 5 . 1199 . November 2021 . 34584544 . 8422400 . 10.3892/etm.2021.10633 .
  10. Jia M, Li C, Zheng Y, Ding X, Chen M, Ding J, Du R, Lu M, Hu G . 6 . Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation . The International Journal of Neuropsychopharmacology . 20 . 11 . 886–895 . November 2017 . 29016795 . 5737563 . 10.1093/ijnp/pyx062 . free .
  11. Shi XR, Hong ZY, Liu HR, Zhang YC, Zhu YZ . Neuroprotective effects of SCM198 on 6-hydroxydopamine-induced behavioral deficit in rats and cytotoxicity in neuronal SH-SY5Y cells . Neurochemistry International . 58 . 8 . 851–860 . July 2011 . 21093517 . 10.1016/j.neuint.2010.11.007 . 33986318 .
  12. Liao L, Zhou M, Wang J, Xue X, Deng Y, Zhao X, Peng C, Li Y . 6 . Identification of the Antithrombotic Mechanism of Leonurine in Adrenalin Hydrochloride-Induced Thrombosis in Zebrafish via Regulating Oxidative Stress and Coagulation Cascade . Frontiers in Pharmacology . 12 . 742954 . 4 November 2021 . 34803688 . 8600049 . 10.3389/fphar.2021.742954 . free .
  13. Huang L, Xu DQ, Chen YY, Yue SJ, Tang YP . Leonurine, a potential drug for the treatment of cardiovascular system and central nervous system diseases . Brain and Behavior . 11 . 2 . e01995 . February 2021 . 33300684 . 7882174 . 10.1002/brb3.1995 .
  14. Wang R, Peng L, Lv D, Shang F, Yan J, Li G, Li D, Ouyang J, Yang J . 6 . Leonurine Attenuates Myocardial Fibrosis Through Upregulation of miR-29a-3p in Mice Post-myocardial Infarction . Journal of Cardiovascular Pharmacology . 77 . 2 . 189–199 . February 2021 . 33235025 . 10.1097/FJC.0000000000000957 . 227168673 .
  15. Zhu Q, Cai W, Sha X, Ma G, Zheng Y, Shi X, Zhu Y . Quantification of leonurine, a novel potential cardiovascular agent, in rat plasma by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in rats . Biomedical Chromatography . 26 . 4 . 518–523 . April 2012 . 21882210 . 10.1002/bmc.1699 .
  16. Liu XH, Pan LL, Deng HY, Xiong QH, Wu D, Huang GY, Gong QH, Zhu YZ . 6 . Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4 . Free Radical Biology & Medicine . 54 . 93–104 . January 2013 . 23127783 . 10.1016/j.freeradbiomed.2012.10.555 .
  17. Xie YZ, Zhang XJ, Zhang C, Yang Y, He JN, Chen YX . Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2-related factor 2 pathway . CNS Neuroscience & Therapeutics . 25 . 9 . 1006–1017 . September 2019 . 31087454 . 6698971 . 10.1111/cns.13146 .
  18. Li F, Zhu S, Jiang Q, Hou C, Pang T, Zhang L, Li W . Novel Stachydrine-Leonurine Conjugate SL06 as a Potent Neuroprotective Agent for Cerebral Ischemic Stroke . ACS Chemical Neuroscience . 12 . 13 . 2478–2490 . July 2021 . 34180238 . 10.1021/acschemneuro.1c00200 . 235660771 .
  19. Liu H, Zhang X, Du Y, Ji H, Li S, Li L, Xing Y, Zhang X, Dong L, Wang C, Zhao K, Ji Y, Cao X . 6 . Leonurine protects brain injury by increased activities of UCP4, SOD, CAT and Bcl-2, decreased levels of MDA and Bax, and ameliorated ultrastructure of mitochondria in experimental stroke . Brain Research . 1474 . 73–81 . September 2012 . 22842526 . 10.1016/j.brainres.2012.07.028 . 24119195 .
  20. Qiu LN, Tan YR, Luo YJ, Chen XJ . Leonurine protects against influenza A virus infection-induced pneumonia in mice . Pathogens and Disease . 79 . 7 . ftab045 . September 2021 . 34543397 . 10.1093/femspd/ftab045 .
  21. Zhuang Q, Ruan L, Jin T, Zheng X, Jin Z . Anti-leukaemia effects of leonurine in vitro and in vivo . General Physiology and Biophysics . 40 . 5 . 397–407 . September 2021 . 34602453 . 10.4149/gpb_2021018 . free .
  22. Liu HM, Guo CL, Zhang YF, Chen JF, Liang ZP, Yang LH, Ma YP . Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy . Frontiers in Pharmacology . 12 . 657724 . 2021 . 33935775 . 8087248 . 10.3389/fphar.2021.657724 . free .
  23. Mao F, Zhang L, Cai MH, Guo H, Yuan HH . Leonurine hydrochloride induces apoptosis of H292 lung cancer cell by a mitochondria-dependent pathway . Pharmaceutical Biology . 53 . 11 . 1684–1690 . 2 November 2015 . 25856714 . 10.3109/13880209.2014.1001406 . 207526411 . free .
  24. Lin M, Pan C, Xu W, Li J, Zhu X . Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins . Drug Design, Development and Therapy . 14 . 1885–1895 . 15 May 2020 . 32523334 . 7237110 . 10.2147/DDDT.S252112 . free .
  25. Li X, Xie Y, Qu W, Ou X, Ou X, Wang C, Qi X, Wang Y, Liu Z, Zhu L . 6 . Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide . Current Drug Metabolism . 21 . 13 . 1060–1067 . November 2020 . 33198612 . 10.2174/1389200221999201116142742 . 226985047 .
  26. Zhu Q, Zhang J, Yang P, Tan B, Liu X, Zheng Y, Cai W, Zhu Y . 6 . Characterization of metabolites of leonurine (SCM-198) in rats after oral administration by liquid chromatography/tandem mass spectrometry and NMR spectrometry . TheScientificWorldJournal . 2014 . 947946 . 2014 . 24772041 . 3956552 . 10.1155/2014/947946 . free .

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