AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties

Narender R. Gavva, Rami Tamir, Yusheng Qu, Lana Klionsky, T. J. Zhang, David Immke, Judy Wang, Dawn Zhu, Todd W Vanderah, Frank Porreca, Elizabeth M. Doherty, Mark H. Norman, Kenneth D. Wild, Anthony W. Bannon, Jean Claude Louis, James J S Treanor

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)474-484
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number1
DOIs
StatePublished - Apr 2005

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Capsaicin
Hyperalgesia
Inhibitory Concentration 50
Animal Models
Pain
Freund's Adjuvant
vanilloid receptor subtype 1
3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide
Calcitonin Gene-Related Peptide
Spinal Ganglia
Neuralgia
Sensory Receptor Cells
Locomotion
G-Protein-Coupled Receptors
Ion Channels
Cations
Protons
Hot Temperature
Pharmacology
Ligands

ASJC Scopus subject areas

  • Pharmacology

Cite this

AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. / Gavva, Narender R.; Tamir, Rami; Qu, Yusheng; Klionsky, Lana; Zhang, T. J.; Immke, David; Wang, Judy; Zhu, Dawn; Vanderah, Todd W; Porreca, Frank; Doherty, Elizabeth M.; Norman, Mark H.; Wild, Kenneth D.; Bannon, Anthony W.; Louis, Jean Claude; Treanor, James J S.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 313, No. 1, 04.2005, p. 474-484.

Research output: Contribution to journalArticle

Gavva, NR, Tamir, R, Qu, Y, Klionsky, L, Zhang, TJ, Immke, D, Wang, J, Zhu, D, Vanderah, TW, Porreca, F, Doherty, EM, Norman, MH, Wild, KD, Bannon, AW, Louis, JC & Treanor, JJS 2005, 'AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties', Journal of Pharmacology and Experimental Therapeutics, vol. 313, no. 1, pp. 474-484. https://doi.org/10.1124/jpet.104.079855
Gavva, Narender R. ; Tamir, Rami ; Qu, Yusheng ; Klionsky, Lana ; Zhang, T. J. ; Immke, David ; Wang, Judy ; Zhu, Dawn ; Vanderah, Todd W ; Porreca, Frank ; Doherty, Elizabeth M. ; Norman, Mark H. ; Wild, Kenneth D. ; Bannon, Anthony W. ; Louis, Jean Claude ; Treanor, James J S. / AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 313, No. 1. pp. 474-484.
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AU - Gavva, Narender R.

AU - Tamir, Rami

AU - Qu, Yusheng

AU - Klionsky, Lana

AU - Zhang, T. J.

AU - Immke, David

AU - Wang, Judy

AU - Zhu, Dawn

AU - Vanderah, Todd W

AU - Porreca, Frank

AU - Doherty, Elizabeth M.

AU - Norman, Mark H.

AU - Wild, Kenneth D.

AU - Bannon, Anthony W.

AU - Louis, Jean Claude

AU - Treanor, James J S

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N2 - 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.

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