The tetrahydrobiopterin pathway and pain

Alasdair M. Naylor, Kevin R. Pojasek, Andrew L. Hopkins, Julian Blagg

    Research output: Contribution to journalReview articlepeer-review

    10 Citations (Scopus)

    Abstract

    Novel approaches for treating chronic pain are required to address a widely recognized, yet largely underserved and unmet, clinical need. The recently discovered link between tetrahydrobiopterin (BH4) synthesis and pain in preclinical models and humans provides a promising new approach for treating neuropathic and other forms of chronic pain. The rate-limiting enzyme in BH4 synthesis, guanosine triphosphate cyclohydrolase 1 (GCH1), and sepiapterin reductase (SPR) are both promising drug targets based on initial active-site characterization of the SARs of these two enzymes. Reducing the elevated BH4 levels associated with pain to baseline, while maintaining sufficient BH4 levels to limit side effects is the goal of discovery programs for novel therapeutics targeting GCH1 or SPR.

    Original languageEnglish
    Pages (from-to)19-30
    Number of pages12
    JournalCurrent Opinion in Investigational Drugs
    Volume11
    Issue number1
    Publication statusPublished - Jan 2010

    Keywords

    • Chronic pain
    • GCH1 pain-protective haplotype
    • guanosine triphosphate cyclohydrolase 1 (GCH1)
    • neuropathic pain
    • sepiapterin reductase (SPR)
    • tetrahydrobiopterin (BH4)
    • GTP CYCLOHYDROLASE-I
    • FEEDBACK REGULATORY PROTEIN
    • TRANSITION-STATE ANALOG
    • SEPIAPTERIN REDUCTASE
    • NEUROPATHIC PAIN
    • CRYSTAL-STRUCTURE
    • NITRIC-OXIDE
    • POTENTIAL INHIBITORS
    • ENDOTHELIAL FUNCTION
    • CARDIOVASCULAR RISK

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