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Functional Properties of the High-Affinity TRPV1 (VR1) Vanilloid Receptor Antagonist (4-Hydroxy-5-iodo-3-methoxyphenylacetate ester) Iodo-Resiniferatoxin

The Journal of Pharmacology and Experimental Therapeutics, ISSN: 0022-3565, Vol: 303, Issue: 3, Page: 1052-1060
2002
  • 124
    Citations
  • 0
    Usage
  • 60
    Captures
  • 3
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    124
  • Captures
    60
  • Mentions
    3
    • References
      3
      • Wikipedia
        3

Article Description

We have synthesized iodinated resiniferatoxin bearing a 4-hydroxy-5-iodo-3-methoxyphenylacetate ester (I-RTX) and have characterized its activity on rat and human TRPV1 (VR1) receptors, as well as in behavioral assays of nociception. In whole cell patch-clamp recordings from transfected cells the functional activity of I-RTX was determined. Currents activated by capsaicin exhibited characteristic outward rectification and were antagonized by capsazepine and I-RTX. On rat TRPV1 the affinity of I-RTX was 800-fold higher than that of capsazepine (IC 50 = 0.7 and 562 nM, respectively) and 10-fold higher on rat versus human receptors (IC 50 = 0.7 and 5.4 nM, respectively). The same difference was observed when comparing the inhibition of [ 3 H]RTX binding to rat and human TRPV1 membranes for both RTX and I-RTX. Additional pharmacological differences were revealed using protons as the stimulus. Under these conditions capsazepine only partly blocked currents through rat TRPV1 receptors (by 70 to 80% block), yet was a full antagonist on human receptors. In contrast, I-RTX completely blocked proton-induced currents in both species and that activated by noxious heat. I-RTX also blocked capsaicin-induced firing of C-fibers in a rat in vitro skin-nerve assay. Despite this activity and the high affinity of I-RTX for rat TRPV1, only capsazepine proved to be an effective antagonist of capsaicin-induced paw flinching in rats. Thus, although I-RTX has limited utility for in vivo behavioral studies it is a high-affinity TRPV1 receptor antagonist that will be useful to characterize the functional properties of cloned and native vanilloid receptor subtypes in vitro.

Bibliographic Details

Seabrook, Guy R; Sutton, Kathy G; Jarolimek, Wolfgang; Hollingworth, Gregory J; Teague, Simon; Webb, Janine; Clark, Natalie; Boyce, Susan; Kerby, Julie; Ali, Zahid; Chou, Margaret; Middleton, Richard; Kaczorowski, Gregory; Jones, A Brian

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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