生物活性

• 靶点	Adenosine Receptor A2A Ki:2.2nM

• 描述A_2A receptor (A_2AR) with Ki of 2.2 nM. The affinity of it for the A_2AR is 70-fold greater than that for the A₁ receptor PMID: 11319241. Istradefylline binds to A₁R, A_2AR, and A₃R in human with Kis of >287 nM, 9.12 nM, and >681 nM, respectively, 50.9 nM and 1.57 nM for A₁R and A_2AR in rat, 105.02 nM and 1.87 nM for A₁R and A_2AR in mouse, respectively ^[6]. Istradefylline causes concentration-dependent abolition of bFGF induction of astrogliosis in primary rat striatal astrocytes ^[7]. The ED50s of istradefylline in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, istradefylline is over 10 times as potent in these models. Istradefylline also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of istradefylline and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A_2AR antagonist istradefylline and dopaminergic agents ^[8]. Istradefylline (3.3 mg/kg, i.p.) treatment before a single dose of MPTP attenuates the partial dopamine and DOPAC depletions measured in striata 1 week later ^[9]. Oral administration of istradefylline protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. It also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice ^[10].

• 动物研究
  剂量	Rat: 0.16 mg/kg - 2.5 mg/kg[3] (p.o.) Marmoset: 10 mg/kg[4] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[5] Dose 3 mg/kg Administration p.o. MRT 11.8 h AUC0→24h 6100 ± 501 ng·h/ml T1/2 13.1 h Tmax 2.8 ± 2.0 h Cmax 618 ± 105 ng/ml AUC0→∞ 7340 ng·h/ml CL/F 0.409 L/h/kg AUC0→t 6650 ± 748 ng·h/ml