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Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

Nicole Urban, Liming Wang, Sandra Kwiek, Jörg Rademann, Wolfgang M Kuebler, Michael Schaefer

Mol Pharmacol. 2016 Jan;89(1):197-213.

PMID: 26500253

Abstract:

Classical or canonical transient receptor potential 6 (TRPC6), a nonselective and Ca(2+)-permeable cation channel, mediates pathophysiological responses within pulmonary and renal diseases that are still poorly controlled by current medication. Thus, controlling TRPC6 activity may provide a promising and challenging pharmacological approach. Recently identified chemical entities have demonstrated that TRPC6 is pharmacologically targetable. However, isotype-selectivity with regard to its closest relative, TRPC3, is difficult to achieve. Reasoning that balsams, essential oils, or incense materials that are traditionally used for inhalation may contain biologic activities to block TRPC6 activity, we embarked on a natural compound strategy to identify new TRPC6-blocking chemical entities. Within several preparations of plant extracts, a strong TRPC6-inhibitory activity was found in conifer balsams. The biologic activity was associated with nonvolatile resins, but not with essential oils. Of various conifers, the larch balsam was unique in displaying a marked TRPC6-prevalent mode of action. By testing the main constituents of larch resin, we identified larixol and larixyl acetate as blockers of Ca(2+) entry and ionic currents through diacylglycerol- or receptor-activated recombinant TRPC6 channels, exhibiting approximately 12- and 5-fold selectivity compared with its closest relatives TRPC3 and TRPC7, respectively. No significant inhibition of more distantly related TRPV or TRPM channels was seen. The potent inhibition of recombinant TRPC6 by larixyl acetate (IC50 = 0.1-0.6 µM) was confirmed for native TRPC6-like [Ca(2+)]i signals in diacylglycerol-stimulated rat pulmonary artery smooth muscle cells. In isolated mouse lungs, larix-6-yl monoacetate (CAS 4608-49-5; larixyl acetate; 5 µM) prevented acute hypoxia-induced vasoconstriction. We conclude that larch-derived labdane-type diterpenes are TRPC6-selective inhibitors and may represent a starting point for pharmacological TRPC6 modulation within experimental therapies.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP4608495	Larixyl acetate		4608-49-5	Price

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