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Istradefylline

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Chemical Structure| 155270-99-8 同义名 : KW-6002
CAS号 : 155270-99-8
货号 : A791038
分子式 : C20H24N4O4
纯度 : 98%
分子量 : 384.429
MDL号 : MFCD00928421
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 25 mg/mL(65.03 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

30% propylene glycol+5% Tween 80+65% water 30 mg/mL suspension

生物活性
靶点

  • Adenosine Receptor

    Adenosine A2A receptor, Ki:2.2 nM
描述 A2A receptor (A2AR) with Ki of 2.2 nM. The affinity of it for the A2AR is 70-fold greater than that for the A1 receptor [11]. Istradefylline binds to A1R, A2AR, 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 A2AR in rat, 105.02 nM and 1.87 nM for A1R and A2AR 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 A2AR 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].
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT02073981 - Active, not recruiting December 2019 Japan ... 展开 >> Juntendo University Hospital Bunkyo-ku, Tokyo, Japan, 113-8431 收起 <<
NCT00006337 Parkinson's Disease Phase 2 Completed - United States, Maryland ... 展开 >> National Institute of Neurological Disorders and Stroke (NINDS) Bethesda, Maryland, United States, 20892 收起 <<
NCT00199368 Parkinson's Disease Phase 3 Completed - United States, New Jersey ... 展开 >> Kyowa Pharmaceutical Inc. Princeton, New Jersey, United States, 08540 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.60mL

0.52mL

0.26mL

13.01mL

2.60mL

1.30mL

26.01mL

5.20mL

2.60mL
参考文献

[1]Chen JF, Xu K, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci. 2001 May 15;21(10):RC143.

[2]Kanda T, Jackson MJ, et al. Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000 Apr;162(2):321-7.

[3]Yamada K, Kobayashi M, et al. Antidepressant-like activity of the adenosine A(2A) receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents. Pharmacol Biochem Behav. 2013 Dec;114-115:23-30.

[4]Uchida S, Soshiroda K, et al. The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets. Eur J Pharmacol. 2015 Nov 5;766:25-30.

[5]KW-6002

[6]Mihara T. Pharmacological characterization of a novel, potent adenosine A1 and A2A receptor dual antagonist, 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in models of Parkinson's disease and cognition. J Pharmacol Exp Ther. 2007 Nov;323(2):708-19.

[7]Brambilla R. Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes. Glia. 2003 Aug;43(2):190-4.

[8]Shiozaki S. Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP. Psychopharmacology (Berl). 1999 Nov;147(1):90-5.

[9] Chen JF. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci. 2001 May 15;21(10)

[10]Ikeda K. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. J Neurochem. 2002 Jan;80(2):262-70. doi: 10.1046/j.0022-3042.2001.00694.x.

[11]Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, Sonsalla PK, Castagnoli K, Castagnoli N Jr, Schwarzschild MA. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci. 2001 May 15;21(10):RC143. doi: 10.1523/JNEUROSCI.21-10-j0001.2001. PMID: 11319241; PMCID: PMC6762498.