Pyrazine-Fused Triterpenoids Block the TRPA1 Ion Channel in Vitro and Inhibit TRPA1-Mediated Acute Inflammation in Vivo

Ilari Mäki-Opas, Mari Hämäläinen, Lauri J. Moilanen, Raisa Haavikko, Tiina J. Ahonen, Sami Alakurtti, Vânia M. Moreira, Katsuhiko Muraki, Jari Yli-Kauhaluoma, Eeva Moilanen (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    9 Citations (Scopus)


    TRPA1 is a nonselective cation channel, most famously expressed in nonmyelinated nociceptors. In addition to being an important chemical and mechanical pain sensor, TRPA1 has more recently appeared to have a role also in inflammation. Triterpenoids are natural products with anti-inflammatory and anticancer effects in experimental models. In this paper, 13 novel triterpenoids were created by synthetically modifying betulin, an abundant triterpenoid of the genus Betula L., and their TRPA1-modulating properties were examined. The Fluo 3-AM protocol was used in the initial screening, in which six of the 14 tested triterpenoids inhibited TRPA1 in a statistically significant manner. In subsequent whole-cell patch clamp recordings, the two most effective compounds (pyrazine-fused triterpenoids 8 and 9) displayed a reversible and dose- and voltage-dependent effect to block the TRPA1 ion channel at submicromolar concentrations. Interestingly, the TRPA1 blocking action was also evident in vivo, as compounds 8 and 9 both alleviated TRPA1 agonist-induced acute paw inflammation in mice. The results introduce betulin-derived pyrazine-fused triterpenoids as promising novel antagonists of TRPA1 that are potentially useful in treating diseases with a TRPA1-mediated adverse component.

    Original languageEnglish
    Pages (from-to)2848-2857
    Number of pages10
    JournalACS Chemical Neuroscience
    Issue number6
    Publication statusPublished - 19 Jun 2019
    MoE publication typeA1 Journal article-refereed


    • inflammation
    • natural compounds
    • pain
    • transient receptor potential channels
    • triterpenoids
    • TRPA1


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