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, 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.' '
Appendino
Giovanni
G
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Novara, Italy.
Daddario
Nives
N
Minassi
Alberto
A
Moriello
Aniello Schiano
AS
De Petrocellis
Luciano
L
Di Marzo
Vincenzo
V
D001966:Bromine / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002713:Chlorine / Q000737:chemistry; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007455:Iodine / Q000737:chemistry*; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels
D004224:Diterpenes; D007473:Ion Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C468130:iodoresiniferatoxin; D002713:Chlorine; D007455:Iodine; D002211:Capsaicin; C040937:nonivamide; D001966:Bromine; D002118:Calcium