Istradefylline Adenosine Receptor Antagonist

The affinity of Istradefylline for the A2AR is 70-fold greater than that for the A1 receptor with K_i of 2.2 nM versus 150 nM. [1] Exposure of primary rat striatal astrocytes to this compound results in concentration-dependent abolition of bFGF induction of astrogliosis in vitro. [5] Binding affinities (K_i) of this chemical for A1 receptor, A2A receptor, and A3 receptor in human are >287 nM, 9.12 nM, and >681 nM, respectively, for A1 receptor and A2A receptor in rat 50.9 nM and 1.57 nM, respectively, and for A1 receptor and A2A receptor in mouse 105.02 nM and 1.87 nM, respectively. [6]

Istradefylline reverses CGS21680-induced and reserpine-induced catalepsy with ED50 of 0.05 mg/kg and 0.26 mg/kg, respectively. This compound is over 10 times as potent in these models compared to other adenosine antagonists and dopamine agonist drugs. Administration of this chemical in combination with LevoDOPA (50 mg/kg) exerts prominent effects on haloperidol-induced and reserpine-induced catalepsy. [2] Oral administration of this compound at 10 mg/kg to MPTP-treated common marmosets produces an increase in locomotor activity to approximately twice that of control and improves motor disability. Administration of this chemical (10 mg/kg, po, 90 minutes before SKF80723/quinpirole/LevoDOPA) in combination with SKF80723 (1 mg/kg, ip), quinpirole (0.06 mg/kg ip), or LevoDOPA (2.5 mg/kg po) produces a significant additive effect on locomotor activity and improvement of motor disability but not dyskinesia. [3] In the MPTP mice model, this compound significantly attenuates striatal dopamine depletion under various conditions. Pretreatment with this chemical (3.3 mg/kg, i.p.) before a single dose of MPTP attenuates the partial dopamine and DOPAC depletions measured in striata 1 week later. [1] Oral administration of this compound protects against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats, and prevents the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. [4] Chronic treatment with this compound does not improve the reversal deficits in dopamine-depleted rats. [7] The tremulous jaw movements induced by pimozide are significantly reduced by co-administration of either this chemical or tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression are reduced by a behaviorally effective dose of this compound, in contrast to tropicamide by which c-Fos expression in pimozide-treated rats is actually increased. [8]