The taming of capsaicin. Reversal of the vanilloid activity of N-acylvanillamines by aromatic iodination

J Med Chem. 2005 Jul 14;48(14):4663-9. doi: 10.1021/jm050139q.


Aromatic iodination ortho to the phenolic hydroxyl reverts the activity of the ultrapotent vanilloid agonist resiniferatoxin (RTX, 1a), generating the ultrapotent antagonist 5'-iodoRTX (1b). 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.' '

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bromine / chemistry
  • Calcium / metabolism
  • Capsaicin / analogs & derivatives*
  • Capsaicin / chemical synthesis*
  • Capsaicin / chemistry
  • Capsaicin / pharmacology
  • Cell Line
  • Chlorine / chemistry
  • Diterpenes / chemistry
  • Diterpenes / pharmacology
  • Humans
  • Iodine / chemistry*
  • Ion Channels / agonists
  • Ion Channels / antagonists & inhibitors*
  • Structure-Activity Relationship
  • TRPV Cation Channels


  • Diterpenes
  • Ion Channels
  • TRPV Cation Channels
  • TRPV1 protein, human
  • iodoresiniferatoxin
  • Chlorine
  • Iodine
  • Capsaicin
  • nonivamide
  • Bromine
  • Calcium