Abstract
Leucettamols, bifunctionalized sphingoid-like compounds obtained from a marine sponge Leucetta sp., act as non-electrophilic activators of the TRPA1 channel and potent inhibitors of the icilin-mediated activation of the TRPM8 channel, while they are inactive on CB₁, CB₂ and TRPV1 receptors. Leucettamols represent the first compounds of marine origin to target TRPA1 and the first class of natural products to inhibit TRPM8 channels. The preparation of a small series of semi-synthetic derivatives revealed interesting details on the structure-activity relationships within this new chemotype of simple acyclic TRP modulators.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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HEK293 Cells
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Humans
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Porifera / chemistry*
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Rats
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Receptor, Cannabinoid, CB1 / drug effects
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / drug effects
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Receptor, Cannabinoid, CB2 / metabolism
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Sphingolipids / chemistry
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Sphingolipids / isolation & purification
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Sphingolipids / pharmacology*
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Structure-Activity Relationship
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TRPA1 Cation Channel
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TRPC Cation Channels / drug effects*
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TRPC Cation Channels / metabolism
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TRPM Cation Channels / antagonists & inhibitors*
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TRPM Cation Channels / metabolism
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TRPV Cation Channels / drug effects
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TRPV Cation Channels / metabolism
Substances
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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Sphingolipids
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TRPA1 Cation Channel
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TRPC Cation Channels
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TRPM Cation Channels
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TRPV Cation Channels
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TRPV1 protein, human
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Trpa1 protein, rat
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Trpm8 protein, rat
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leucettamol A