Istradefylline
[CAS# 155270-99-8]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein) >> Adenosine receptor antagonist
• Name: Istradefylline
• Synonyms: 8-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methylpurine-2,6-dione; KW-6002
• Molecular Formula: C₂₀H₂₄N₄O₄
• Molecular Weight: 384.43
• CAS Registry Number: 155270-99-8
• EC Number: 803-302-8
• SMILES: CCN1C2=C(C(=O)N(C1=O)CC)N(C(=N2)/C=C/C3=CC(=C(C=C3)OC)OC)C

Properties

• Solubility: 92 mg/mL (DMSO), <1.2 mg/mL (water), <1.2.mg/mL (ethanol) (Expl.)

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06 Danger
• Risk Statements: H301
• Safety Statements: P264-P270-P301+P316-P321-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Reproductive toxicity	Repr.	2	H361

Discovery and Applications

Istradefylline is a chemical compound that has garnered attention for its therapeutic potential in the treatment of Parkinson's disease. It is an adenosine A2A receptor antagonist, and its mechanism of action involves modulating the activity of the neurotransmitter dopamine in the brain. The compound has been studied extensively for its ability to complement existing treatments for Parkinson’s disease, particularly those that address motor symptoms.

The discovery of istradefylline traces back to the search for compounds that could selectively block the adenosine A2A receptor. This receptor is primarily located in the basal ganglia, an area of the brain involved in motor control. In Parkinson’s disease, the balance between dopamine and adenosine signaling is disrupted, leading to motor dysfunction. Adenosine A2A receptor antagonism has been proposed as a strategy to restore this balance, providing symptom relief for patients. Istradefylline was identified as a promising candidate due to its selective binding to the A2A receptor and its ability to modulate dopamine-related pathways.

Istradefylline was initially developed and tested in clinical trials for its ability to enhance the effects of levodopa, the primary treatment for Parkinson’s disease. Levodopa helps replenish dopamine levels in the brain, but over time its effectiveness diminishes, and patients may experience fluctuations in symptom control. Istradefylline was found to improve motor symptoms when added to levodopa therapy, particularly in patients with advanced Parkinson’s disease. Its ability to modulate the A2A receptor helped reduce the motor fluctuations commonly seen with long-term levodopa use.

The compound’s development culminated in its approval in Japan as an adjunct treatment for Parkinson’s disease in patients who experience “off” episodes, when medication effectiveness wanes. Istradefylline is marketed under the brand name Nourianz in Japan and has undergone clinical trials in other regions, though it has not yet received approval in countries like the United States or Europe.

Beyond Parkinson’s disease, research is ongoing to explore the broader potential of istradefylline in other neurological and psychiatric disorders. Because of its action on the adenosine A2A receptor, it may also be beneficial in conditions where adenosine signaling is implicated, such as certain neurodegenerative diseases, depression, and cognitive disorders. However, further studies are necessary to fully understand its therapeutic scope.

References

1998. Adenosine A2A Antagonist: A novel antiparkinsonian agent that does not provoke dyskinesia in Parkinsonian monkeys. Annals of Neurology, 43, 4.
DOI: 10.1002/ana.410430415

2024. Parkinson disease therapy: current strategies and future research priorities. Nature reviews. Neurology, 20, 11.
DOI: 10.1038/s41582-024-01034-x

2001. Selective adenosine A2A receptor antagonists. Farmaco (Societa chimica italiana : 1989), 56, 3.
DOI: 10.1016/s0014-827x(01)01024-2