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

doi:10.1016/j.bmcl.2009.11.035

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

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-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.

Original language	English
Pages (from-to)	97-99
Number of pages	3
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2009.11.035
Publication status	Published - 1 Jan 2010

Keywords

Capsaicin
Resiniferatoxin (RTX)
Structure-activity relationships
TRPV1
Vanilloids

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10.1016/j.bmcl.2009.11.035

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

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.",

keywords = "Capsaicin, Resiniferatoxin (RTX), Structure-activity relationships, TRPV1, Vanilloids",

author = "Giovanni Appendino and Abdellah Ech-Chahad and Alberto Minassi and \{De Petrocellis\}, Luciano and Marzo, \{Vincenzo Di\}",

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doi = "10.1016/j.bmcl.2009.11.035",

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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

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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 - https://www.scopus.com/pages/publications/72149094339

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DO - 10.1016/j.bmcl.2009.11.035

M3 - Article

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 1

ER -

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

Abstract

Keywords

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