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Research ArticleNeuropharmacology

7-tert-Butyl-6-(4-Chloro-Phenyl)-2-Thioxo-2,3-Dihydro-1H-Pyrido[2,3-d]Pyrimidin-4-One, a Classic Polymodal Inhibitor of Transient Receptor Potential Vanilloid Type 1 with a Reduced Liability for Hyperthermia, Is Analgesic and Ameliorates Visceral Hypersensitivity

Mark S. Nash, Peter McIntyre, Alex Groarke, Elliot Lilley, Andrew Culshaw, Allan Hallett, Moh Panesar, Alyson Fox and Stuart Bevan
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 389-398; DOI: https://doi.org/10.1124/jpet.112.191932
Mark S. Nash
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Peter McIntyre
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Alex Groarke
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Elliot Lilley
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Andrew Culshaw
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Allan Hallett
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Moh Panesar
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Alyson Fox
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Stuart Bevan
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Abstract

The therapeutic potential of transient receptor potential vanilloid type 1 (TRPV1) antagonists for chronic pain has been recognized for more than a decade. However, preclinical and clinical data revealed that acute pharmacological blockade of TRPV1 perturbs thermoregulation, resulting in hyperthermia, which is a major hurdle for the clinical development of these drugs. Here, we describe the properties of 7-tert-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (BCTP), a TRPV1 antagonist with excellent analgesic properties that does not induce significant hyperthermia in rodents at doses providing maximal analgesia. BCTP is a classic polymodal inhibitor of TRPV1, blocking activation of the human channel by capsaicin and low pH with IC50 values of 65.4 and 26.4 nM, respectively. Similar activity was observed with rat TRPV1, and the inhibition by BCTP was competitive and reversible. BCTP also blocked heat-induced activation of TRPV1. In rats, the inhibition of capsaicin-induced mechanical hyperalgesia was observed with a D50 value of 2 mg/kg p.o. BCTP also reversed visceral hypersensitivity and somatic inflammatory pain, and using a model of neuropathic pain in TRPV1 null mice we confirmed that its analgesic properties were solely through the inhibition of TRPV1. We were surprised to find that BCTP administered orally induced only a maximal 0.6°C increase in core body temperature at the highest tested doses (30 and 100 mg/kg), contrasting markedly with N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide (AMG517), a clinically tested TRPV1 antagonist, which induced marked hyperthermia (>1°C) at doses eliciting submaximal reversal of capsaicin-induced hyperalgesia. The combined data indicate that TRPV1 antagonists with a classic polymodal inhibition profile can be identified where the analgesic action is separated from the effects on body temperature.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.112.191932.

  • ABBREVIATIONS:

    TRPV1
    transient receptor potential vanilloid type 1
    CRD
    colorectal distension
    VMR
    visceromotor response
    IBS
    irritable bowel syndrome
    ANOVA
    analysis of variance
    DMSO
    dimethyl sulfoxide
    CHO
    Chinese hamster ovary
    CFA
    complete Freund's adjuvant
    TNBS
    trinitrobenzene sulfonic acid
    BCTP
    7-tert-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one
    AMG517
    N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide
    AMG8562
    (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide
    WIN
    55212-2,(2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate.

  • Received January 14, 2012.
  • Accepted May 4, 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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Research ArticleNeuropharmacology

BCTP, a TRPV1 Inhibitor with Reduced Hyperthermia

Mark S. Nash, Peter McIntyre, Alex Groarke, Elliot Lilley, Andrew Culshaw, Allan Hallett, Moh Panesar, Alyson Fox and Stuart Bevan
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 389-398; DOI: https://doi.org/10.1124/jpet.112.191932

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Research ArticleNeuropharmacology

BCTP, a TRPV1 Inhibitor with Reduced Hyperthermia

Mark S. Nash, Peter McIntyre, Alex Groarke, Elliot Lilley, Andrew Culshaw, Allan Hallett, Moh Panesar, Alyson Fox and Stuart Bevan
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 389-398; DOI: https://doi.org/10.1124/jpet.112.191932
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