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

Abstract

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
Volume10
Issue number6
DOIs
Publication statusPublished - 19 Jun 2019
MoE publication typeA1 Journal article-refereed

Keywords

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

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    Mäki-Opas, I., Hämäläinen, M., Moilanen, L. J., Haavikko, R., Ahonen, T. J., Alakurtti, S., Moreira, V. M., Muraki, K., Yli-Kauhaluoma, J., & Moilanen, E. (2019). Pyrazine-Fused Triterpenoids Block the TRPA1 Ion Channel in Vitro and Inhibit TRPA1-Mediated Acute Inflammation in Vivo. ACS Chemical Neuroscience, 10(6), 2848-2857. https://doi.org/10.1021/acschemneuro.9b00083