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.

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.

• Authors: 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
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 313 Issue 1 Pg. 474-84 (Apr 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15615864 (Publication Type: Journal Article)

Chemical References

• 3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide
• Acrylamides
• Bridged Bicyclo Compounds, Heterocyclic
• Protons
• Receptors, Drug
• Freund's Adjuvant
• Calcitonin Gene-Related Peptide
• Capsaicin

Topics

• Acrylamides (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• CHO Cells
• Calcitonin Gene-Related Peptide (metabolism)
• Capsaicin (antagonists & inhibitors)
• Cells, Cultured
• Cricetinae
• Freund's Adjuvant
• Ganglia, Spinal (cytology, drug effects, metabolism)
• Hot Temperature
• Humans
• Hyperalgesia (chemically induced, drug therapy)
• Inflammation (complications, pathology)
• Motor Activity (drug effects)
• Neurons (drug effects, metabolism)
• Pain Measurement (drug effects)
• Patch-Clamp Techniques
• Protons
• Psychomotor Performance (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Drug (antagonists & inhibitors)
• Transfection