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Molecular Pharmacology Fast Forward
First published on January 2, 2008; DOI: 10.1124/mol.107.042663

0026-895X/08/7304-1225-1234$20.00
Mol Pharmacol 73:1225-1234, 2008

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Activation of TRPA1 by Farnesyl Thiosalicylic Acid

Michael Maher, Hong Ao, Tue Banke, Nadia Nasser, Nyan-Tsz Wu, J. Guy Breitenbucher, Sandra R. Chaplan, and Alan D. Wickenden

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, California

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 J2, 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.

Received October 15, 2007; accepted December 31, 2007

Address correspondence to: Dr. Alan D. Wickenden, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121. E-mail: awickend{at}prdus.jnj.com






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