title: Potency of irritation by benzylidenemalononitriles in humans correlates with TRPA1 ion channel activation.
abstract: We show that the physiological activity of solid aerosolized benzylidenemalononitriles (BMNs) including 'tear gas' (CS) in historic human volunteer trials correlates with activation of the human transient receptor potential ankyrin 1 ion channel (hTRPA1). This suggests that the irritation caused by the most potent of these compounds results from activation of this channel. We prepared 50 BMNs and measured their hTRPA1 agonist potencies. A mechanism of action consistent with their physiological activity, involving their dissolution in water on contaminated body surfaces, cell membrane penetration and reversible thiolation by a cysteine residue of hTRPA1, supported by data from nuclear magnetic resonance experiments with a model thiol, explains the structure-activity relationships. The correlation provides evidence that hTRPA1 is a receptor for irritants on nociceptive neurons involved in pain perception; thus, its activation in the eye, nose, mouth and skin would explain the symptoms of lachrymation, sneezing, coughing and stinging, respectively. The structure-activity results and the use of the BMNs as pharmacological tools in future by other researchers may contribute to a better understanding of the TRPA1 channel in humans (and other animals) and help facilitate the discovery of treatments for human diseases involving this receptor.
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lindsay
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Green
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Bird
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: James T A
authors.initials: JT
authors.lastname: Jones
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Riches
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: McKee
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sandford
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Wakefield
authors.affiliation: Defence Science and Technology Laboratory (Dstl) , Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Timperley
keywords: 2-chlorobenzylidenemalononitrile; TRPA1; benzylidenemalononitriles; irritancy; riot control agent; tear gas