Starting from resiniferonol orthophenylacetate (ROPA, 2) and commercial 5-iodovanillin (5a), a convenient synthesis of the ultrapotent vanilloid antagonist 5′-iodoresiniferatoxin (1a) was achieved, overcoming the problems involved in the direct iodination of either resiniferatoxin (1b) or homovanillic acid (3a).
WahlP, FogedC, TullinS, ThomsenC. (2001) Iodo-resiniferatoxin, a new potent vanilloid receptor antagonist. Molecular Pharmacology, 59, 9–15.
5.
The K(i) value for I-RTX after two hour incubation with cells transfected with TRPV1 has been estimated to be 4.2 pM (LazarJ, BraunDC, TothA, WangY, PearceLV, PavlyukovetsVA, BlumbergPM, GarfieldSH, WincovitchS, ChoiHK, LeeJ. (2006) Kinetics of penetration influence the apparent potency of vanilloids on TRPV1. Molecular Pharmacology, 69, 1166–1173).
6.
TrevisaniM, MilanA, GattiZ, ZanasiA, HarrisonS, FontanaG, MoriceAH, GeppettiP. (2004) Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax, 59, 769–772.
7.
RigoniM, TrevisaniM, MazzieriD, NadalettoR, TognettoM, CreminonC, DavisJB, CampiB, AmatesiS, GeppettiP, HarrisnonS. (2003) Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin. British Journal of Pharmacology, 138, 977–985.
8.
AppendinoG, DaddarioN, MinassiA, Schiano MorelloA, De PetrocellisL, Di MarzoV. (2005) The taming of capsaicin. Reversal of vanilloid activity of N-acylvanillamines by aromatic iodination. Journal of Medicinal Chemistry, 48, 4663–4669.
9.
McDonnelME, ZhangSP, DubinAE, DaxSL. (2002) Synthesis and in vitro evaluation of a novel iodinated resiniferatoxin derivative that is an agonist at the human vanilloid VR1 receptor. Bioorganic & Medicinal Chemistry Letters, 12, 1189–1192.
10.
SeabrookGR, SuttonKG, JarolimekW, HollingworthJH, TeagueS, WebbJ, ClarkN, BoyceS, KerbyJ, LaiZ, ChouM, MiddletonR, KaczorowskiG, JonesAB. (2002) Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. Journal of Pharmacology and Experimental Therapeutics, 303, 1052–1060.
11.
The price of RTX in the 2006 Sigma Catalogue is 280,60 Euro/1mg
12.
FattorussoE, LanzottiV, Taglialatela-ScafatiO, TronGC, AppendinoG. (2002) Bisnorsesquiterpenoids from Euphorbia resinifera Berg. and an expeditious procedure to obtain resiniferatoxin from its fresh latex. European Journal of Organic Chemistry, 71–78.
13.
CastanetA-S, ColobertF, BroutinP-E. (2002) Mild and regioselective iodination of electron-rich aromatics with N-iodosuccinimide and catalytic trifluoroacetic acid. Tetrahedron Letters, 43, 5047–5048
14.
AppendinoG, MinassiA, DaddarioN, BianchiF, TronGC. (2002) Chemoselective esterification of phenolic acids and alcohols. Organic Letters, 4, 3839–3841.
15.
The price of homovanillic acid in the 2006 Aldrich Catalogue is 12,10 Euro/100mg, while 5-iodovanillin is over 50 times cheaper (12,00 Euro/5 g).
16.
AoyamaT, ShioiriT. (1980) Trimethylsilyldiazomethane, a new, stable, and safe reagent for the classical Arndt-Eisert synthesis. Tetrahedron Letters, 21, 4461–4462.
17.
NewmanMS, BealPF. (1950) An improved Wolff rearrangement in homogeneous medium. Journal of American Chemical Society, 72, 5163–5165.
18.
AndersonNG, LustDA, ColapretKA, SimpsonJH, MalleyME, GougoutasJZ. (1996) Sulfonation with inversion by Mitsunobu reaction: An improvement on the original conditions. Journal of Organic Chemistry, 61, 7955–7962.
