A (+)-Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6
| Autor: | Martina Kannler, Alexander Dietrich, Peter Mayer, Michael Schaefer, Dirk Trauner, Stephanie Häfner, Nicole Urban, Johannes Broichhagen, Finn Burg |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Gene isoform Biochemistry TRPC6 Small Molecule Libraries 03 medical and health sciences Transient receptor potential channel chemistry.chemical_compound 0302 clinical medicine TRPC3 Drug Discovery TRPC6 Cation Channel Animals Humans General Pharmacology Toxicology and Pharmaceutics TRPC Cation Channels Pharmacology Natural product Molecular Structure Chemistry Organic Chemistry HEK 293 cells Rats Electrophysiology HEK293 Cells 030104 developmental biology Gene Expression Regulation Acetylation Molecular Medicine Diterpenes 030217 neurology & neurosurgery |
| Zdroj: | ChemMedChem. 13:1028-1035 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201800021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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