TY - JOUR
T1 - Structure-activity relationships of the ultrapotent vanilloid resiniferatoxin (RTX)
T2 - The side chain benzylic methylene
AU - Appendino, Giovanni
AU - Ech-Chahad, Abdellah
AU - Minassi, Alberto
AU - De Petrocellis, Luciano
AU - Marzo, Vincenzo Di
PY - 2010/1/1
Y1 - 2010/1/1
N2 - The side chain benzylic methylene is a critical element for the vanilloid activity of resiniferatoxin (2a, RTX), and introduction of branching, oxygen functions, or isosteric substitution at this center proved detrimental, with a decrease of potency of 2-3 orders of magnitude compared to the natural product. Conversely, only a modest erosion of activity was observed upon α-methylation and α-methylenation of the side chain. Surprisingly, introduction of an iodine atom in the guaiacyl moiety of the oxygen isoster 2h led to an unexpected and remarkable (>1000-fold) increase of potency, affording 2i, a compound that outperforms RTX in terms of vanilloid agonism and represents the first one-digit picomolar ligand of a TRP channel discovered to date.
AB - The side chain benzylic methylene is a critical element for the vanilloid activity of resiniferatoxin (2a, RTX), and introduction of branching, oxygen functions, or isosteric substitution at this center proved detrimental, with a decrease of potency of 2-3 orders of magnitude compared to the natural product. Conversely, only a modest erosion of activity was observed upon α-methylation and α-methylenation of the side chain. Surprisingly, introduction of an iodine atom in the guaiacyl moiety of the oxygen isoster 2h led to an unexpected and remarkable (>1000-fold) increase of potency, affording 2i, a compound that outperforms RTX in terms of vanilloid agonism and represents the first one-digit picomolar ligand of a TRP channel discovered to date.
KW - Capsaicin
KW - Resiniferatoxin (RTX)
KW - Structure-activity relationships
KW - TRPV1
KW - Vanilloids
UR - http://www.scopus.com/inward/record.url?scp=72149094339&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2009.11.035
DO - 10.1016/j.bmcl.2009.11.035
M3 - Article
SN - 0960-894X
VL - 20
SP - 97
EP - 99
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 1
ER -