A non-pungent triprenyl phenol of fungal origin, scutigeral, stimulates rat dorsal root ganglion neurons via interaction at vanilloid receptors

1 A [H-3]-resiniferatoxin (RTX) binding assay utilizing rat spinal cord membranes was employed to identify novel vanilloids in a collection of natural products of fungal origin. Of the five active compounds found (scutigeral, acetyl-scutigeral, ovinal, neogrifolin, and methyl-neogrifolin), scutigeral (K-i=19 mu M), isolated from the edible mushroom Albatrellus ovinus, was selected for further characterization. 2 Scutigeral induced a dose-dependent Ca-45 uptake by rat dorsal root ganglion neurons with an EC50 of 1.6 mu M, which was fully inhibited by the competitive vanilloid receptor antagonist capsazepine (IC50 = 5.2 mu M). 3 [H-3]-RTX binding isotherms were shifted by scutigeral (10-80 mu M) in a competitive manner. The Schild plot of the data had a slope of 0.8 and gave an apparent K-d estimate for scutigeral of 32 mu M. 4 Although in the above assays scutigeral mimicked capsaicin, it was not pungent on the human tongue up to a dose of 100 nmol per tongue, nor did it provoke protective wiping movements in the rat (up to 100 mu M) upon intraocular instillation. 5 In accord with being non-pungent, scutigeral (5 mu M) did not elicit a measurable inward current in isolated rat dorsal root ganglion neurons under voltage-clamp conditions. It did, however, reduce the proportion of neurons (from 61 to 15%) that responded to a subsequent capsaicin (1 mu M) challenge. In these neurons, scutigeral both delayed (from 27 to 72 s) and diminished (from 5.0 to 1.9 nA) the maximal current evoked by capsaicin. 6 In conclusion, scutigeral and its congeners form a new chemical class of vanilloids, the triprenyl phenols. Scutigeral promises to be a novel chemical lead for the development of orally active, non-pungent vanilloids.