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. Moilainen, Raisa Haavikko, Tiina J. Ahonen, Sami Alakurtti, Vânia M. Moreira, Katsuhiko Muraki, Jari Yli-Kauhaluoma, Eeva Moilainen

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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
Early online date29 Apr 2019
Publication statusPublished - 19 Jun 2019


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


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