116
SPR-Inhibitors in the field of Neuropathic Pain with an upside In Inflammation/Autoimmune
Lead Discovery Center
Small molecule
Neurology
Hit To Lead or Lead Optimization
• Tetrahydrobiopterin (BH4) critically involved in nociceptive signaling.
• Tetrahydrobiopterin (BH4) is an enzyme cofactor for various aromatic amino acid hydroxylases, including phenylalanine, tyrosine and tryptophan hydroxylases, as well as being an important cofactor for other enzymes such as the nitric oxide synthases (inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS)), and alkylglycerol monooxygenase. As such, BH4 is involved in regulating production of various neurotransmitters (e.g., serotonin and dopamine) and nitric oxide. Deficiencies in BH4 are associated with deficiencies in neurotransmitters including serotonin and dopamine. Reduced BH4 production is also associated with reduced pain sensitivity after injury.
• Basic principle: Tetrahydrobiopterin (BH4) critically involved in nociceptive signaling
➢ humans: gene-variants of GTP cyclohydrolase 1 (rate-limiting step in BH4 synthesis) effectively modulates pain
➢ (i) BH4 levels increased in injured sensory neurons, (ii) BH4 induces nitric oxide (NO) biosynthesis, (iii) NO important transmitter involved in nociceptive processes, (iv) blockade of sepiapterin reductase (SPR) effectively blocks BH4 production (in vitro & in vivo validation)
WO2017059191A1
Peripheral tetrahydrobiopterin is involved in the pathogenesis of mechanical hypersensitivity in a rodent postsurgical pain model. PAIN. (2020)
