Kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) is the expression product of the KMO (gene). It participates in tryptophan metabolism through the kynurenine catabolic pathway. Kynurenine 3-hydroxylase catalyzes the insertion of molecular oxygen into the aromatic ring of kynurenine to produce 3-hydroxy-l-kynurenine. In addition, Kynurenine 3-hydroxylase metabolism of kynurenine increases in response to elevated substrate levels and upregulation in KMO expression, both associated with neuroinflammation. Kynurenine 3-hydroxylase serves as an important branch point in the kynurenine pathway. As a result, changes in Kynurenine 3-hydroxylase expression or activity may contribute to the development of neurodegenerative, neuropsychiatric, and neurodevelopmental diseases.
Ro 61-8048 is a potent, high-affinity and orally active kynurenine 3-hydroxylase inhibitor. In a microdialysis experiment in rats, Ro 61-8048 provokes a significant increase of extracellular kynurenic acid concentrations. In addition, Ro 61-8048 blocks rat and gerbil kynurenine 3-hydroxylase after oral administration. Importantly, Ro 61-8048 has the potential for study the kynurenine pathway in certain neurological disorders, in particular neuroinflammation. Furthermore, Ro 61-8048 provokes kynurenic acid in the striatum, cerebellum and brainstem of mutant hamsters. Moreover, intrastriatal injections of Ro 61-8048 significantly reduces the severity of dystonia in dtsz hamsters without leading to marked central side effects. Thus, Ro 61-8048 is an interesting candidate for striatal dysfunction.
To sum up, Ro 61-8048 is a potent, brain-penetrant and orally active kynurenine 3-hydroxylase inhibitor, with antidystonic, anticonvulsant and neuroprotective activities.