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Research ArticleNeuropharmacology

Pharmacological Characterization of (3S)-3-(Hydroxymethyl)-4-(5-Methylpyridin-2-yl)-N-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-3,4-Dihydro-2H-Benzo[b][1,4]Oxazine-8-Carboxamide (JTS-653), a Novel Transient Receptor Potential Vanilloid 1 Antagonist

Yoshihiro Kitagawa, Atsuko Miyai, Kenji Usui, Yuji Hamada, Katsuya Deai, Masashi Wada, Yoshihisa Koga, Masahiro Sakata, Mikio Hayashi, Makoto Tominaga and Mutsuyoshi Matsushita
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 520-528; DOI: https://doi.org/10.1124/jpet.112.194027
Yoshihiro Kitagawa
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Atsuko Miyai
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Kenji Usui
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Yuji Hamada
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Katsuya Deai
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Masashi Wada
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Yoshihisa Koga
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Masahiro Sakata
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Mikio Hayashi
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Makoto Tominaga
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Mutsuyoshi Matsushita
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Abstract

Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [3H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA2 values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC50 values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC50 values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.112.194027.

  • ABBREVIATIONS:

    TRP
    transient receptor potential
    TRPV
    TRP vanilloid
    AMG8562
    (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide
    AS1928370
    (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide
    2-APB
    2-aminoethyl diphenylborinate
    4α-PDD
    4α-phorbol-12,13-didecanoate, RTX, resiniferatoxin
    HEK
    human embryonic kidney
    RLU
    relative light unit
    TRPM8
    transient receptor potential melastatin 8
    TRPA1
    transient receptor potential ankyrin 1
    MES
    4-morpholineethanesulfonic acid
    PWT
    paw withdrawal threshold
    PWL
    paw withdrawal latency
    ABT-102
    (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea
    AMG517
    N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide
    SB-705498
    N-(2-bromophenyl)-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea
    JNJ-39729209
    (2-(2,6-dichlorobenzyl)thiazolo(5,4-d)pyrimidin-7-yl)-(4-trifluoromethylphenyl)amine
    A-425619
    1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea
    JYL-1421
    N-(4-tert-butylbenzyl)-N′-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea
    JTS-653
    (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide.

  • Received March 5, 2012.
  • Accepted May 14, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Pharmacological Characterization of (3S)-3-(Hydroxymethyl)-4-(5-Methylpyridin-2-yl)-N-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-3,4-Dihydro-2H-Benzo[b][1,4]Oxazine-8-Carboxamide (JTS-653), a Novel Transient Receptor Potential Vanilloid 1 Antagonist
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Research ArticleNeuropharmacology

Pharmacological Profile of a Novel TRPV1 Antagonist, JTS-653

Yoshihiro Kitagawa, Atsuko Miyai, Kenji Usui, Yuji Hamada, Katsuya Deai, Masashi Wada, Yoshihisa Koga, Masahiro Sakata, Mikio Hayashi, Makoto Tominaga and Mutsuyoshi Matsushita
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 520-528; DOI: https://doi.org/10.1124/jpet.112.194027

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Research ArticleNeuropharmacology

Pharmacological Profile of a Novel TRPV1 Antagonist, JTS-653

Yoshihiro Kitagawa, Atsuko Miyai, Kenji Usui, Yuji Hamada, Katsuya Deai, Masashi Wada, Yoshihisa Koga, Masahiro Sakata, Mikio Hayashi, Makoto Tominaga and Mutsuyoshi Matsushita
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 520-528; DOI: https://doi.org/10.1124/jpet.112.194027
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