title: The tetrahydrobiopterin pathway and pain.
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.
authors.affiliation: Solace Pharmaceuticals Ltd, 6 Denne Hill Business Centre, Denne Hill Farm, Womenswold, Canterbury, Kent CT5 3PJ, UK. alasdairnaylor@solacepharma.com
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Naylor
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Pojasek
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hopkins
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055808:Drug Discovery; D006136:GTP Cyclohydrolase / Q000378:metabolism; D006801:Humans; D010146:Pain / Q000235:genetics / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D001708:Biopterins; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D006136:GTP Cyclohydrolase; C003402:sapropterin