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
- 124Citations
- 60Captures
- 3Mentions
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Metrics Details
- Citations124
- Citation Indexes123
- 123
- CrossRef100
- Patent Family Citations1
- Patent Families1
- Captures60
- Readers60
- 60
- Mentions3
- References3
- Wikipedia3
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
http://www.sciencedirect.com/science/article/pii/S0022356524360409; http://dx.doi.org/10.1124/jpet.102.040394; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0036894895&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/12438527; https://linkinghub.elsevier.com/retrieve/pii/S0022356524360409; https://dx.doi.org/10.1124/jpet.102.040394; https://jpet.aspetjournals.org/content/303/3/1052
Elsevier BV
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