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 mem branes 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), scutigera l (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 gangl ion neurons with an EC50 of 1.6 mu M, which was fully inhibited by the comp etitive 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 pu ngent on the human tongue up to a dose of 100 nmol per tongue, nor did it p rovoke protective wiping movements in the rat (up to 100 mu M) upon intraoc ular instillation. 5 In accord with being non-pungent, scutigeral (5 mu M) did not elicit a me asurable 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) challen ge. In these neurons, scutigeral both delayed (from 27 to 72 s) and diminis hed (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 chemic al lead for the development of orally active, non-pungent vanilloids.