title: Activation of TRPA1 by farnesyl thiosalicylic acid.
abstract: The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of calcium fluorescent assays and whole-cell electrophysiology, we discovered several compounds that possess potent, selective TRPA1-activating activity, including several lipid compounds (farnesyl thiosalicylic acid, farnesyl thioacetic acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), and 5,8,11,14-eicosatetraynoic acid), and two marketed drugs: disulfiram (Antabuse; a compound used in the treatment of alcohol abuse) and the antifungal agent chlordantoin. Farnesyl thiosalicylic acid activates the channel in excised patches and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Maher
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.forename: Tue
authors.initials: T
authors.lastname: Banke
authors.forename: Nadia
authors.initials: N
authors.lastname: Nasser
authors.forename: Nyan-Tsz
authors.initials: NT
authors.lastname: Wu
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004594:Electrophysiology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005453:Fluorescence; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology*; D000074025:TRPA1 Cation Channel; D014162:Transfection; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D012459:Salicylates; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C093323:farnesylthiosalicylic acid; D012430:Ruthenium Red; D005204:Farnesol; C004471:allyl isothiocyanate; D002118:Calcium