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Vol. 303, Issue 3, 1052-1060, December 2002
The Neuroscience Research Centre, Merck Sharp and Dohme, Harlow,
Essex, United Kingdom (G.R.S., K.G.S., W.J., G.J.H., S.T., J.W., N.C.,
S.B., J.K., Z.A., A.B.J.); and Merck Research Laboratories, Rahway, New
Jersey (M.C., R.M., G.K.)
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.
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