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Potency of irritation by benzylidenemalononitriles in humans correlates with TRPA1 ion channel activation. | LitMetric

AI Article Synopsis

  • The study investigates how solid aerosolized benzylidenemalononitriles (BMNs), like tear gas (CS), activate the hTRPA1 ion channel, linking this activation to physiological irritation effects experienced by humans.
  • Researchers prepared and tested 50 different BMNs for their ability to activate hTRPA1, revealing a mechanism that explains how these compounds irritate senses like eyesight and breathing through interactions with the body.
  • The findings suggest that hTRPA1 plays a key role in pain perception and may lead to advancements in understanding and treating various human diseases related to this receptor.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448789PMC
http://dx.doi.org/10.1098/rsos.140160DOI Listing

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