Oxime derivatives related to AP18: Agonists and antagonists of the TRPA1 receptor

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 1, 2010, Pages 276-279

  DeFalco, Jeff ^a   Steiger, Daniel ^a   Gustafson, Amy ^a   Emerling, Daniel E ^a   Kelly, Michael G ^a   Duncton, Matthew A J ^a  

^a EVOTEC AG   (Germany)

Author keywords

Agonist; Ankyrin repeat Transient Receptor Potential 1; Antagonist; AP18; Oxime; Transient Receptor Potential; TRP; TRPA1

Indexed keywords

ANKYRIN REPEAT TRANSIENT RECEPTOR POTENTIAL CHANNEL 1; ANTIINFLAMMATORY AGENT; AP 18; OXIME DERIVATIVE; TRANSIENT RECEPTOR POTENTIAL CHANNEL 1; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; ARTICLE; DRUG STRUCTURE; IC 50; NONHUMAN; STRUCTURE ACTIVITY RELATION;

CALCIUM CHANNELS; HUMANS; NERVE TISSUE PROTEINS; OXIMES; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSIENT RECEPTOR POTENTIAL CHANNELS;

EID: 72049089819     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.10.113     Document Type: Article

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25. See Supplementary data for experimental procedures and a representative copy of the agonist and antagonist dose-response graphs for each compound described in this Letter.
26. A representative selection of substituted cinnamaldehyde and benzylideneacetone derivatives related to the oximes described in Table 1 were also tested for their ability to act as TRPA1 ligands. In each case, we found that the compounds functioned as TRPA1 agonists.
27. See Ref. 8b for the ability of AP18 5 to act as an antagonist of TRPA1 when cinnamaldehyde, iodoacetamide, mustard oil (allyl isothiocyanate) and noxious cold were used as agonists. Confirmation of the antagonist properties of AP18 using electrophysiology experiments are also described in Ref. 8b.
28. A reviewer of this manuscript proposed that compounds 5 and 11 could also act as antagonists by 'binding' in the same pocket as cinnamaldehyde. However, the presence of additional methyl substitutions prevented reaction with the cysteine residues of TRPA1. We think this hypothesis to be unlikely, since literature suggests that chemical modulation of TRPA1 is dictated by the reactivity of a molecule, rather than its shape (see Refs. 1 and 4 for further information).