A (+)-Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6

Stephanie Häfner, Finn Burg, Martina Kannler, Nicole Urban, Peter Mayer, Alexander Dietrich, Dirk Trauner, Johannes Broichhagen, Michael Schaefer

Research output: Contribution to journalArticle

Abstract

Natural products have many health benefits, and their application can improve the quality of life. Recently, the diterpene (+)-larixol and its acetylated congeners demonstrated selective inhibition of the second-messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expanded these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing high-throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, termed SH045, as a compound with nanomolar affinity and 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells. Expanding on this finding, TRPC6 inhibition was also observed in rat pulmonary smooth muscle cells. Furthermore, treatment of isolated perfused lung preparations with SH045 led to a decrease in lung ischemia-reperfusion edema (LIRE), a life-threatening condition associated with TRPC6 that may occur after organ transplantation. Taken together, and given the inexpensive, straightforward, and scalable preparation of SH045, we report a TRPC6 blocker that holds promise for the translational treatment of LIRE.

Original languageEnglish (US)
Pages (from-to)1028-1035
Number of pages8
JournalChemMedChem
Volume13
Issue number10
DOIs
StatePublished - May 23 2018

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Keywords

  • LIRE
  • TRPC6
  • diterpenes
  • labdane
  • larixol

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Häfner, S., Burg, F., Kannler, M., Urban, N., Mayer, P., Dietrich, A., Trauner, D., Broichhagen, J., & Schaefer, M. (2018). A (+)-Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6. ChemMedChem, 13(10), 1028-1035. https://doi.org/10.1002/cmdc.201800021