The Taming of Capsaicin. Reversal of the Vanilloid Activity of N-Acylvanillamines by Aromatic Iodination

Aromatic iodination ortho to the phenolic hydroxyl reverts the activity of the ultrapotent vanilloid agonist resiniferatoxin (RTX, <BO>1a</BO>), generating the ultrapotent antagonist 5‘-iodoRTX (<BO>1b</BO>). To better understand the role of iodine in this remarkable switch of activity, a systematic investigation on the halogenation of vanillamides, a class of compounds structurally simpler than resiniferonoids, was carried out. The results showed that (a) the antagonistic activity depends on the site of halogenation and is maximal at C-6‘, (b) iodine is more efficient than chlorine and bromine at reverting the agonistic activity, and (c) iodine−carbon exchange decreases antagonist activity. Iodine-induced reversal of vanilloid activity was also observed in vanillamides more powerful than capsaicin, but a poor correlation was found between agonistic and antagonistic potencies, suggesting that differences exist in the way vanillamides and their 6‘-iodo derivatives bind to TRPV1.‘ ‘