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Research ArticleNeuropharmacology

Amelioration of Neuropathic Pain by Novel Transient Receptor Potential Vanilloid 1 Antagonist AS1928370 in Rats without Hyperthermic Effect

Tomonari Watabiki, Tetsuo Kiso, Takahiro Kuramochi, Koichi Yonezawa, Noriko Tsuji, Atsuyuki Kohara, Shuichiro Kakimoto, Toshiaki Aoki and Nobuya Matsuoka
Journal of Pharmacology and Experimental Therapeutics March 2011, 336 (3) 743-750; DOI: https://doi.org/10.1124/jpet.110.175570
Tomonari Watabiki
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Tetsuo Kiso
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Takahiro Kuramochi
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Koichi Yonezawa
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Noriko Tsuji
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Atsuyuki Kohara
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Shuichiro Kakimoto
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Toshiaki Aoki
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Nobuya Matsuoka
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Abstract

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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.175570.

  • ABBREVIATIONS:

    TRPV1
    transient receptor potential vanilloid 1
    RTX
    resiniferatoxin
    AMG517
    N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide
    SB-366791
    N-(3-methoxyphenyl)-4-chlorocinnamide
    AS1928370
    (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide
    BCTC
    N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide
    HEK
    human embryonic kidney
    TRP
    transient receptor potential channel
    TRPV4
    transient receptor potential vanilloid 4
    TRPA1
    transient receptor potential ankyrin 1
    TRPM8
    transient receptor potential melastatin 8
    SNL
    spinal nerve ligation
    CFA
    complete Freund's adjuvant
    ANOVA
    analysis of variance
    CI
    confidence interval
    A-425619
    1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea
    CCI
    chronic constriction injury
    AMG8562
    (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide
    BAPTA
    bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid.

  • Received September 26, 2010.
  • Accepted November 19, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleNeuropharmacology

Amelioration of Neuropathic Pain by Novel Transient Receptor Potential Vanilloid 1 Antagonist AS1928370 in Rats without Hyperthermic Effect

Tomonari Watabiki, Tetsuo Kiso, Takahiro Kuramochi, Koichi Yonezawa, Noriko Tsuji, Atsuyuki Kohara, Shuichiro Kakimoto, Toshiaki Aoki and Nobuya Matsuoka
Journal of Pharmacology and Experimental Therapeutics March 1, 2011, 336 (3) 743-750; DOI: https://doi.org/10.1124/jpet.110.175570

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Research ArticleNeuropharmacology

Amelioration of Neuropathic Pain by Novel Transient Receptor Potential Vanilloid 1 Antagonist AS1928370 in Rats without Hyperthermic Effect

Tomonari Watabiki, Tetsuo Kiso, Takahiro Kuramochi, Koichi Yonezawa, Noriko Tsuji, Atsuyuki Kohara, Shuichiro Kakimoto, Toshiaki Aoki and Nobuya Matsuoka
Journal of Pharmacology and Experimental Therapeutics March 1, 2011, 336 (3) 743-750; DOI: https://doi.org/10.1124/jpet.110.175570
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