Structure-activity relationships of the ultrapotent vanilloid resiniferatoxin (RTX): The side chain benzylic methylene

Giovanni Appendino, Abdellah Ech-Chahad, Alberto Minassi, Luciano De Petrocellis, Vincenzo Di Marzo

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

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.

Lingua originaleInglese
pagine (da-a)97-99
Numero di pagine3
RivistaBioorganic and Medicinal Chemistry Letters
Volume20
Numero di pubblicazione1
DOI
Stato di pubblicazionePubblicato - 1 gen 2010

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