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Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin.
J Pharmacol Exp Ther. 2002 Dec; 303(3):1052-60.JP

Abstract

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 (IC50 = 0.7 and 562 nM, respectively) and 10-fold higher on rat versus human receptors (IC50 = 0.7 and 5.4 nM, respectively). The same difference was observed when comparing the inhibition of [3H]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.

Authors+Show Affiliations

The Neuroscience Research Centre, Merck Sharp and Dohme, Harlow, Essex, United Kingdom. seabrook@merck.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

12438527

Citation

Seabrook, Guy R., et al. "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, vol. 303, no. 3, 2002, pp. 1052-60.
Seabrook GR, Sutton KG, Jarolimek W, et al. Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J Pharmacol Exp Ther. 2002;303(3):1052-60.
Seabrook, G. R., Sutton, K. G., Jarolimek, W., Hollingworth, G. J., Teague, S., Webb, J., Clark, N., Boyce, S., Kerby, J., Ali, Z., Chou, M., Middleton, R., Kaczorowski, G., & Jones, A. B. (2002). 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, 303(3), 1052-60.
Seabrook GR, et al. Functional Properties of the High-affinity TRPV1 (VR1) Vanilloid Receptor Antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate Ester) Iodo-resiniferatoxin. J Pharmacol Exp Ther. 2002;303(3):1052-60. PubMed PMID: 12438527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. AU - Seabrook,Guy R, AU - Sutton,Kathy G, AU - Jarolimek,Wolfgang, AU - Hollingworth,Gregory J, AU - Teague,Simon, AU - Webb,Janine, AU - Clark,Natalie, AU - Boyce,Susan, AU - Kerby,Julie, AU - Ali,Zahid, AU - Chou,Margaret, AU - Middleton,Richard, AU - Kaczorowski,Gregory, AU - Jones,A Brian, PY - 2002/11/20/pubmed PY - 2002/12/27/medline PY - 2002/11/20/entrez SP - 1052 EP - 60 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 303 IS - 3 N2 - 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 (IC50 = 0.7 and 562 nM, respectively) and 10-fold higher on rat versus human receptors (IC50 = 0.7 and 5.4 nM, respectively). The same difference was observed when comparing the inhibition of [3H]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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12438527/Functional_properties_of_the_high_affinity_TRPV1__VR1__vanilloid_receptor_antagonist__4_hydroxy_5_iodo_3_methoxyphenylacetate_ester__iodo_resiniferatoxin_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12438527 DB - PRIME DP - Unbound Medicine ER -