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

A [ 3 H]‐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 μ M ), isolated from the edible mushroom Albatrellus ovinus , was selected for further characterization. Scutigeral induced a dose‐dependent 45 Ca uptake by rat dorsal root ganglion neurons with an EC 50 of 1.6 μ M , which was fully inhibited by the competitive vanilloid receptor antagonist capsazepine (IC 50 =5.2 μ M ). [ 3 H]‐RTX binding isotherms were shifted by scutigeral (10–80 μ 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 μ M . 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 μ M ) upon intraocular instillation. In accord with being non‐pungent, scutigeral (5 μ 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 μ 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. 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.British Journal of Pharmacology (1999) 126 , 1351–1358; doi: 10.1038/sj.bjp.0702440