Istradefylline

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Description

Istradefylline (KW-6002) is a selective adenosine A2A receptor (A2AR) antagonist with Ki of 2.2 nM. Oral administration of Istradefylline improves motor disability in MPTP-treated parkinsonian marmosets in a dose-dependent manner without provoking dyskinesia. Combination of Istradefylline with a low dose of L-DOPA or with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produces an additive improvement in motor disability but not dyskinesia in MPTP-treated common marmosets. Blockade of A2AR by Istradefylline treatment rescues locomotor impairment in dopamine D2 receptor-deficient mice, with the level of expression of enkephalin and substance P reestablished to normal levels. Istradefylline treatment potentiates rotational behavior induced by dopaminergic drugs in hemi-Parkinsonian rats. Istradefylline treatment alone causes an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly alters the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, Istradefylline does not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. Treatment with Istradefylline prevents the loss of dopaminergic striatal terminals and nigral cell bodies and inhibits the nigral microglia activation in MPTP treated mice. A Phase II study of Istradefylline (monotherapy) and a Phase III study of Istradefylline in combination with levodopa for the treatment of Parkinson’s disease have been completed.

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