TY - JOUR
T1 - The taming of capsaicin. Reversal of the vanilloid activity of N-acylvanillamines by aromatic iodination
AU - Appendino, Giovanni
AU - Daddario, Nives
AU - Minassi, Alberto
AU - Moriello, Aniello Schiano
AU - De Petrocellis, Luciano
AU - Di Marzo, Vincenzo
PY - 2005/7/14
Y1 - 2005/7/14
N2 - 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.″
AB - 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.″
UR - http://www.scopus.com/inward/record.url?scp=22244474357&partnerID=8YFLogxK
U2 - 10.1021/jm050139q
DO - 10.1021/jm050139q
M3 - Article
SN - 0022-2623
VL - 48
SP - 4663
EP - 4669
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -