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

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Citation

Appendino G, Ech-Chahad A, Minassi A, De Petrocellis L, Di Marzo V

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

Bioorg Med Chem Lett. 2010 Jan 1;20(1):97-9. doi: 10.1016/j.bmcl.2009.11.035. Epub 2009 Nov 14.

PubMed ID
19951840 [ View in PubMed
]
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 alpha-methylation and alpha-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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CapsaicinTransient receptor potential cation channel subfamily V member 1EC 50 (nM)40N/AN/ADetails