Synthetic Transformations of Higher Terpenoids. 39. Synthesis and Analgesic Activity of Isopimaric Acid Derivatives

New derivatives of isopimaric acid at the carboxylic acid were prepared. Their analgesic activity was studied in models of visceral and thermal pain. Isopimaric acid amides with aminoethanol and (2R)-(hydroxymethyl)pyrrolidine groups exhibited statistically significant analgesic activity in acetic acid-induced writhing (5 and 25 mg/kg doses) and hot-plate tests (25 mg/kg dose) that was comparable to that of diclofenac sodium (10 mg/kg dose). The new agents were characterized by low (LD50 > 1250 mg/kg) in vivo toxicity. Molecular modeling of possible interaction of the most active compounds with transmembrane G-protein-binding cannabinoid receptor CB2 was performed.

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Fig. 1.


  1. 1.

    M. A. Gromova, Yu. V. Kharitonov, T. V. Rybalova, and E. E. Shul′ts, Chem. Nat. Compd., 55, 871 (2019).

  2. 2.

    G. A. Tolstikov, T. G. Tolstikova, E. E. Shul′ts, S. E. Tolstikov, and M. B. Khvostov, Resinous Acids of Russian Conifers. Chemistry, Pharmacology [in Russian], B. A. Trofimov (ed.), Nauchnoe Izd. GEO, Novosibirsk, 2011, 395 pp.

  3. 3.

    R. M. P. Gutierrez and E. G. Baez, J. Asian Nat. Prod. Res., 13, 934 (2011).

    Article  Google Scholar 

  4. 4.

    S. S. Cheng and S. T. Chang, Wood Sci. Technol., 48, 831 (2014).

    CAS  Article  Google Scholar 

  5. 5.

    H. Cote, M.-A. Boucher, A. Pichette, B. Roger, and J. Legault, J. Ethnopharmacol., 194, 684 (2016).

    CAS  Article  Google Scholar 

  6. 6.

    R. Tanaka, H. Tokuda, and Y. Ezaki, Phytomedicine, 15, 985 (2008).

    CAS  Article  Google Scholar 

  7. 7.

    E. M. Pferschy-Wenzig, O. Kunert, A. Presser, and R. Bauer, J. Agric. Food Chem., 56, 11688 (2008).

    CAS  Article  Google Scholar 

  8. 8.

    J. Zaugg, S. Khom, D. Eigenmann, I. Baburin, M. Hamburger, and S. Hering, J. Nat. Prod., 74, 1764 (2011).

    CAS  Article  Google Scholar 

  9. 9.

    S. Salari, M. S. Ejneby, J. Brask, and F. Elinder, Acta Physiol., 222, e12895 (2018).

  10. 10.

    Y. Imaizumi, K. Sakamoto, A. Yamada, A. Hotta, S. Ohya, K. Muraki, M. Uchiyama, and T. Ohwada, Mol. Pharmacol., 62, 836 (2002).

    CAS  Article  Google Scholar 

  11. 11.

    C. Wu, K. V. Gopal, T. J. Lukas, G. W. Gross, and E. J. Moore, Eur. J. Pharmacol., 732, 68 (2014).

    CAS  Article  Google Scholar 

  12. 12.

    M. K. Hjortness, L. Riccardi, A. Hongdusit, A. Ruppe, M. Zhao, E. Y. Kim, P. H. Zwart, B. Sankaran, H. Arthanari, M. C. Sousa, M. De Vivo, and J. M. Fox, Biochemistry, 57, 5886 (2018).

    CAS  Article  Google Scholar 

  13. 13.

    D. Merk, F. Grisoni, L. Friedrich, E. Gelzinyte, and G. Schneider, J. Med. Chem., 61, 5442 (2018).

    CAS  Article  Google Scholar 

  14. 14.

    R. Russo, J. Loverme, G. L. Rana, G. D’Agostino, O. Sasso, A. Calignano, and D. Piomelli, Eur. J. Pharmacol., 566, 117 (2007).

  15. 15.

    R. M. Labib, R. Srivedavyasasri, F. S. Youssef, and S. A. Ross, Saudi Pharm. J., 26, 437 (2018).

    Article  Google Scholar 

  16. 16.

    H.-C. Lu and K. Mackie, Biol. Psychiatry, 79, 516 (2016).

    CAS  Article  Google Scholar 

  17. 17.

    P. Yang, L. Wang, and X.-Q. Xie, Future Med. Chem., 4, 187 (2012).

    CAS  Article  Google Scholar 

  18. 18.

    M. A. Timoshenko, A. B. Ayusheev, Yu. V. Kharitonov, M. M. Shakirov, and E. E. Shul′ ts, Chem. Nat. Compd., 50, 673 (2014).

  19. 19.

    M. L. Belen′kii, Elements of Quantitative Assessment of Pharmacological Effects [in Russian], Medgiz, Leningrad, 1963, 146 pp.

  20. 20.

    T. Widianti, Y. Hiraga, S. Kojima, and M. Abe, Tetrahedron: Asymmetry, 21, 1861 (2010).

    CAS  Article  Google Scholar 

  21. 21.

    Yu. V. Kharitonov, E. E. Shul′ts, and M. M. Shakirov, Chem. Nat. Compd., 49, 1067 (2014).

  22. 22.

    R. Koster, M. Anderson, and E. J. De Beer, Fed. Proc., 18, 412 (1959).

    Google Scholar 

  23. 23.

    N. B. Eddy and D. Leimbach, J. Pharmacol. Exp. Ther., 107 (3), 385 (1953).

    CAS  PubMed  Google Scholar 

  24. 24.

    Schrodinger Small Molecule Drug Discovery Suite, 2017.

  25. 25.

    E. Harder, W. Damm, J. Maple, C. Wu, M. Reboul, J. Y. Xiang, L. Wang, D. Lupyan, M. K. Dahlgren, J. L. Knight, J. W. Kaus, D. S. Cerutti, G. Krilov, W. L. Jorgensen, R. Abel, and R. A. Friesner, J. Chem. Theory Comput., 12, 281 (2016).

    CAS  Article  Google Scholar 

  26. 26.

    T. Hua, X. Li, L. Wu, C. Iliopoulos-Tsoutsouvas, Y. Wang, M. Wu, L. Shen, C. A. Johnston, S. P. Nikas, F. Song, X. Song, S. Yuan, Q. Sun, Y. Wu, S. Jiang, T. W. Grim, O. Benchama, E. L. Stahl, N. Zvonok, S. Zhao, L. M. Bohn, A. Makriyannis, and Z.-J. Liu, Cell., 180, 655 (2020).

    CAS  Article  Google Scholar 

  27. 27.

    R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, P. C. Sanschagrin, and D. T. Mainz, J. Med. Chem., 49, 6177 (2006).

    CAS  Article  Google Scholar 

  28. 28.

    D. S. Biovia, H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, and T. J. Richmond, J. Chem. Phys., 10, 21 (2000).

    Google Scholar 

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We thank the Khimiya Common Use Center, Siberian Branch, Russian Academy of Sciences, for the spectral and analytical studies. The work was financially supported by an RFBR grant and the Novosibirsk Regional Government (Project No. 19-43-540003).

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Correspondence to E. E. Shul’ts.

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For No. 38, see the literature [1].

Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2021, pp. 404–410.

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Gromova, M.A., Kharitonov, Y.V., Borisov, S.A. et al. Synthetic Transformations of Higher Terpenoids. 39. Synthesis and Analgesic Activity of Isopimaric Acid Derivatives. Chem Nat Compd 57, 474–481 (2021).

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  • diterpenoids
  • isopimaric acid
  • amides
  • esters
  • analgesic activity