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NEUROPHARMACOLOGY
Departments of Neuroscience (N.R.G., R.T., Y.Q., L.K., T.J.Z., D.I., J.W., D.Z., K.D.W., A.W.B., J.-C.L., J.J.S.T.) and Chemistry Research and Discovery (E.M.D., M.H.N.), Amgen Inc., Thousand Oaks, California; and Department of Pharmacology (T.W.V., F.P.), The University of Arizona College of Medicine, Tucson, Arizona
The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide. AMG 9810 is a competitive antagonist of capsaicin activation (IC50 value for human TRPV1, 24.5 ± 15.7 nM; rat TRPV1, 85.6 ± 39.4 nM) and blocks all known modes of TRPV1 activation, including protons (IC50 value for rat TRPV1, 294 ± 192 nM; human TRPV1, 92.7 ± 72.8 nM), heat (IC50 value for rat TRPV1, 21 ± 17 nM; human TRPV1, 15.8 ± 10.8 nM), and endogenous ligands, such as anandamide, N-arachidonyl dopamine, and oleoyldopamine. AMG 9810 blocks capsaicin-evoked depolarization and calcitonin gene-related peptide release in cultures of rat dorsal root ganglion primary neurons. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG 9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. At effective doses, AMG 9810 did not show any significant effects on motor function, as measured by open field locomotor activity and motor coordination tests. AMG 9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.
Address correspondence to: Dr. James J. S. Treanor, Department of Neuroscience, Amgen Inc., MS-29-2-B, Thousand Oaks, CA 91320-1799. E-mail: jtreanor{at}amgen.com
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