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Planta Med 2023; 89(06): 674-682
DOI: 10.1055/a-1956-7542
Natural Product Chemistry & Analytical Studies
Original Papers

Metabolite Profiling of Talatisamine in Heart Tissue After Oral Administration and Analysis of Cardiac Bioactivities

Shuai Huang 
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
3   Yibin Institute of Southwest Jiaotong University, Yibin, Sichuan, P. R. China
,
Yang Lv
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
,
Jian-Zhu Wang
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
,
Mei-Zhen Ye
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
,
Rui-Jie Lu
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
,
Lin Chen
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
,
Jiang Xie
2   The Affiliated Hospital of Southwest Jiaotong University, The Third Peopleʼs Hospital of Chengdu, Chengdu, Sichuan, P. R. China
,
Feng Gao
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
,
Xian-Li Zhou
1   School of Life Science and Engineering Southwest Jiaotong University, Chengdu, Sichuan, P. R. China
2   The Affiliated Hospital of Southwest Jiaotong University, The Third Peopleʼs Hospital of Chengdu, Chengdu, Sichuan, P. R. China
› Author AffiliationsSupported by: the Fundamental Research Funds for Central Universities 2682022ZTPY078
Supported by: National Natural Science Foundation of China 82073734
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Abstract

The lateral roots of the Aconitum carmichaelii (“Fuzi”) have been used for centuries as a cardiotonic in China. The diterpenoid alkaloid talatisamine (TA) is a major bioactive component of Fuzi, but the identity and bioactivities of the TA metabolites have not been examined in detail. In this study, metabolite profiling of TA was performed in rat heart by UPLC-MS following oral administration. Metabolites were identified by comparing protonated molecules, fragmentation patterns, and chromatographic behaviors with those of standard compounds. Metabolites of TA were then prepared and tested for cardiotonic activity on isolated frog hearts. The metabolite cammaconine, a C19 diterpenoid alkaloid with a hydroxyl group at C-18, exhibited substantial cardiotonic activity during frog heart perfusion. To further investigate the structure–cardiac effect relationships, a series of C19-diterpenoid alkaloids with 18-OH were prepared. Eight tested compounds (5–12) demonstrated measurable cardioactivity, of which compound 5 with an N-methyl group and compound 7 with a methoxy at C-16 showed stronger effects on ventricular contraction than the other compounds. Thus, 18-OH is a critical structural feature determining cardiotonic activity, and efficacy is improved by the presence of N-methyl or methoxy at C-16. Preliminary mechanistic studies suggested that the cardiotonic effect of compound 5 is mediated by enhanced cellular calcium influx. Metabolites of TA with these structural features may be useful therapeutics to prevent heart failure.

Key words

Ranunculaceae - Aconitum carmichaelii - Fuzi - diterpenoid alkaloids - talatisamine - metabolism - cammaconine - cammaconine analogs - cardiotonic activity

Supporting Information



Publication History

Received: 28 June 2022

Accepted after revision: 06 October 2022

Accepted Manuscript online:
06 October 2022

Article published online:
18 January 2023

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Jiangsu New Medical College. Dictionary of traditional Chinese Medicine. Shanghai: Shanghai Science and Technology Publishing House; 1995: 228-232 1191–1194
    Google Scholar
  • 2 Chinese Pharmacopoeia Committee. Chinese Pharmacopoeia, 2020 ed. Beijing: Chemical Industry Press; 2020
    Google Scholar
  • 3 Fu YP, Zou YF, Lei FY, Wangensteen H, Inngjerdingen KT. Aconitum carmichaelii Debeaux: A systematic review on traditional use, and the chemical structures and pharmacological properties of polysaccharides and phenolic compounds in the roots. J Ethnopharmacol 2022; 291: 115148
    CrossrefPubMedGoogle Scholar
  • 4 Deng ZJ. Fang Ji Xue. Beijing: China Press of Traditional Chinese Medicine; 2003: 139
    Google Scholar
  • 5 Zhou GH, Tang LY, Zhou XD, Wang T, Kou ZZ, Wang ZJ. A review on phytochemistry and pharmacological activities of the processed lateral root of Aconitum carmichaelii Debeaux. J Ethnopharmacol 2015; 160: 173-193
    CrossrefPubMedGoogle Scholar
  • 6 Wang XY, Zhou QM, Guo L, Dai O, Meng CW, Miao LL, Liu J, Lin Q, Peng C, Xiong L. Cardioprotective effects and concentration-response relationship of aminoalcohol-diterpenoid alkaloids from Aconitum carmichaelii . Fitoterapia 2021; 149: 104822
    CrossrefPubMedGoogle Scholar
  • 7 Li Y, Gao F, Zhang JF, Zhou XL. Four new diterpenoid alkaloids from the roots of Aconitum carmichaelii . Chem Biodivers 2018; 15: e1800147
    CrossrefPubMedGoogle Scholar
  • 8 Song MK, Liu H, Jiang HL, Yue JM, Hu GY, Chen HZ. Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons. Neuroscience 2008; 155: 469-475
    CrossrefPubMedGoogle Scholar
  • 9 Wang YX, Song MK, Hou LN, Yu ZH, Chen HZ. The newly identified K+ channel blocker talatisamine attenuates beta-amyloid oligomers induced neurotoxicity in cultured cortical neurons. Neurosci Lett 2012; 518: 122-127
    CrossrefPubMedGoogle Scholar
  • 10 Demirbağ Karaali M, Aydın Karataş E. Investigation of the potential anticancer effects of napelline and talatisamine dirterpenes on experimental brain tumor models. Cytotechnology 2020; 72: 569-578
    CrossrefPubMedGoogle Scholar
  • 11 Chen MC, Chen YJ, Wang XQ, Zhou YF. Quantitative determination of talatisamine and its pharmacokinetics and bioavailability in mouse plasma by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1124: 180-187
    CrossrefPubMedGoogle Scholar
  • 12 Tan GG, Lou ZY, Jing J, Li WH, Zhu ZY, Zhao L, Zhang GQ, Chai YF. Screening and analysis of aconitum alkaloids and their metabolites in rat urine after oral administration of aconite roots extract using LC-TOFMS-based metabolomics. Biomed Chromatogr 2011; 25: 1343-1351
    CrossrefPubMedGoogle Scholar
  • 13 Yang SP, Zhang HY, Beier RC, Sun FF, Cao XY, Shen JZ, Wang ZH, Zhang SX. Comparative metabolism of lappaconitine in rat and human liver microsomes and in vivo of rat using ultra high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry. J Pharm Biomed Anal 2015; 110: 1-11
    CrossrefPubMedGoogle Scholar
  • 14 Du YF, Huang LY, Wang N, Li XH, Zhou XL, Zhang L, Huang S, Walsh PJ, Gao F. Rhodium-catalyzed direct arylation of furopyridine: Synthesis and the cardiac effects of dictamnine derivatives. Adv Synth Catal 2022; 364: 1002-1008
    CrossrefPubMedGoogle Scholar
  • 15 Liu XX, Jian XX, Cai XF, Chao RB, Chen QH, Chen DL, Wang XL, Wang FP. Cardioactive C19-diterpenoid alkaloids from the lateral roots of Aconitum carmichaeli “Fu Zi”. Chem Pharm Bull 2012; 60: 144-149
    CrossrefPubMedGoogle Scholar
  • 16 Blagbrough I, Hardick D, Wonnacott S, Potter B. Regioselective demethylation of aconitine. Tetrahedron Lett 1994; 35: 3367-3370
    CrossrefPubMedGoogle Scholar
  • 17 Joshi BS, Srivastava SK, Barber AD, Desai HK, Pelletier SW. Selective demethylation of some aconitine-type norditerpenoid alkaloids. J Nat Prod 1997; 60: 439-443
    CrossrefPubMedGoogle Scholar
  • 18 Yue JM, Xu J, Chen YZ, Chen SN. Diterpenoid alkaloids from Aconitum talassicum . Phytochemistry 1994; 37: 1467-1470
    CrossrefPubMedGoogle Scholar
  • 19 Zhang JF, Chen L, Huang S, Shan LH, Gao F, Zhou XL. Diterpenoid alkaloids from two Aconitum species with antifeedant activity against Spodoptera exigua . J Nat Prod 2017; 80: 3136-3142
    CrossrefPubMedGoogle Scholar
  • 20 Zhang X, Zhang J, Chen L. Three new C19-diterpenoid alkaloids from Aconitum apetalum . Heterocycles 2018; 96: 304-310
    CrossrefPubMedGoogle Scholar
  • 21 Lu J, Xu JB, Li XH, Zhou XL, Zhang CG, Gao F. Three new C19-diterpenoid alkaloids from Aconitum novoluridum . Chem Pharm Bull 2021; 69: 811-816
    CrossrefPubMedGoogle Scholar
  • 22 Jiang HY, Huang S, Gao F, Zhen YQ, Li CY, Zhou XL. Diterpenoid alkaloids from Aconitum brevicalcaratum as autophagy inducers. Nat Prod Res 2019; 33: 1741-1746
    CrossrefPubMedGoogle Scholar
  • 23 Hao XJ, Chen SY, Zhou J. Three new diterpenoid alkaloids from Aconitum scaposum . Plant Divers 1985; 2: 217-224
    PubMedGoogle Scholar
  • 24 Hu ZX, An Q, Tang HY, Chen ZH, Aisa HA, Zhang Y, Hao XJ. Acoapetaludines A–K, C20 and C19-diterpenoid alkaloids from the whole plants of Aconitum apetalum (Huth) B. Fedtsch. Phytochemistry 2019; 167: 112111
    CrossrefPubMedGoogle Scholar
  • 25 Xu JJ, Zhao DK, Ai HL, Zhang LM, Xie SQ, Zi SH, Yang SC, Shen Y. Three new C19-diterpenoid alkaloids from Aconitum forrestii . Helv Chim Acta 2013; 96: 2155-2159
    CrossrefPubMedGoogle Scholar
  • 26 Li YH, Chen DH. The alkaloidal constituents from the roots of aconitum brevicalcaratum diels. I. Acta Chim Sin 1994; 52: 204-208
    PubMedGoogle Scholar
  • 27 Sujatha K, Shanmugam P, Perumal PT, Muralidharan D, Rajendran M. Synthesis and cardiac effects of 3, 4-dihydropyrimidin-2-(1H)-one-5 carboxylates. Bioorg Med Chem Lett 2006; 16: 4893-4897
    CrossrefPubMedGoogle Scholar