Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect

J Pharmacol Exp Ther. 2011 Mar;336(3):743-50. doi: 10.1124/jpet.110.175570. Epub 2010 Nov 22.


Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC₅₀ value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca²(+) flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca²(+) flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 μM. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED₅₀ values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain.

Publication types

  • Comparative Study

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Benzamides / therapeutic use*
  • Capsaicin / pharmacology
  • Capsaicin / therapeutic use
  • Fever* / chemically induced
  • HEK293 Cells
  • Humans
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology
  • Pain / drug therapy
  • Pain / physiopathology
  • Pain Measurement / drug effects*
  • Pain Measurement / methods
  • Protein Binding / physiology
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Quinolones / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / physiology


  • Analgesics
  • Benzamides
  • N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-((2-methylpyrrolidin-1-yl)methyl)biphenyl-4-carboxamide
  • Quinolones
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Capsaicin