Istradefylline

Names

[ Name ]:
Istradefylline

[Synonym ]:
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione
1H-Purine-2,6-dione, 3,7-dihydro-1,3-diethyl-8-(2-(3,4-dimethoxyphenyl)ethenyl)-7-methyl-, (E)-
8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
8-[(E)-2-(3,4-Dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methylxanthine
Istradefylline
KW 6002
UNII:2GZ0LIK7T4
8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6-dione
UNII-2GZ0LIK7T4
1H-Purine-2,6-dione, 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-7-methyl-

Biological Activity

[Description]:

Istradefylline is a very potent, selective and orally active adenosine A2A receptor antagonist with Ki of 2.2 nM in experimental models of Parkinson's disease.

[Related Catalog]:

Signaling Pathways >> GPCR/G Protein >> Adenosine Receptor

Research Areas >> Neurological Disease

[Target]

Ki: 2.2 nM (adenosine A2A receptor)

[In Vitro]

Istradefylline has 70-fold greater affinity for the A2AR than the A1 receptor with Ki of 2.2 nM versus 150 nM[1]. Istradefylline causes concentration-dependent abolition of bFGF induction of astrogliosis in primary rat striatal astrocytes[4]. Istradefylline binds to A1 receptor, A2A receptor, and A3 receptor in human with Kis of >287 nM, 9.12 nM, and >681 nM, respectively, 50.9 nM and 1.57 nM for A1 receptor and A2A receptor in rat, 105.02 nM and 1.87 nM for A1 receptor and A2A receptor in mouse, respectively[5].

[In Vivo]

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[1]. Istradefylline reverses CGS21680-induced and reserpine-induced catalepsy with an ED50 of 0.05 mg/kg and 0.26 mg/kg, respectively. Istradefylline is over 10 times as potent in these models compared to other adenosine antagonists and dopamine agonist drugs. Istradefylline combined with L-dopa cuases potent effects on haloperidol-induced and reserpine-induced catalepsy[2]. Istradefylline (10 mg/kg, p.o.) results an increase in locomotor activity to approximately twice that of control and improves motor disability in MPTP-treated common marmosets. Istradefylline (10 mg/kg, p.o.) in combination with SKF80723, quinpirole, or L-DOPA produces a significant additive effect on locomotor activity and improvement of motor disability but not dysKinesia[3].

[Cell Assay]

A CHO cell line permanently expressing the human adenosine A1or A2A receptor is cultured in α-MEM supplemented with 10% (v/v) fetal bovine serum, 50 U/mL penicillin, and 50 μg/mL streptomycin. Cells are grown at 37°C in an environment of 5% CO2. These cells are seeded on black 96-well assay plates at a density of 15,000 cells/well, and then they are cultured for 24 h.

[Animal admin]

The animals are housed either in pairs or alone under standard conditions at a temperature of 24-26°C and 50-60% relative humidity using a 12-h light-dark cycle. Diet consisted of standard food pellets, fresh fruit, and Mazuri marmoset jelly. The animals are treated with MPTP in a dose of 2.0 mg/kg sc daily for 5 days. Following MPTP treatment the animals are allowed to recover from the acute effects over a period of some 6-8 weeks. During MPTP treatment and throughout the following weeks, the animals are hand-fed with Mazuri marmoset jelly and fresh fruit puree until they are able to maintain them-selves. Prior to behavioral testing, from 6-8 weeks to 8 months after exposure to MPTP, all animals show a marked reduction of basal locomotor activity, slower and less coordinated movements, abnormal postures of some parts of the body, and reduced checKing movements and eye blinks. Istradefylline (KW-6002) is suspended in 0.3% Tween-80 and 10% sucrose solution and administered in a final volume of 2.0 mL/kg body weight by oral gavage.

[References]

[1]. Chen JF, 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]. Shiozaki S, et al. 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.

[3]. Kanda T, 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.

[4]. Brambilla R, et al. 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.

[5]. Mihara T, et al. 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 Pharm

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Boiling Point ]:
601.0±65.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₀H₂₄N₄O₄

[ Molecular Weight ]:
384.429

[ Flash Point ]:
317.3±34.3 °C

[ Exact Mass ]:
384.179749

[ PSA ]:
80.28000

[ LogP ]:
2.84

[ Appearance of Characters ]:
white to beige

[ Vapour Pressure ]:
0.0±1.7 mmHg at 25°C

[ Index of Refraction ]:
1.598

[ Storage condition ]:
2-8°C

[ Water Solubility ]:
DMSO: soluble5mg/mL (clear solution)

Safety Information

[ Symbol ]:

GHS06

[ Signal Word ]:
Danger

[ Hazard Statements ]:
H301

[ Precautionary Statements ]:
P301 + P310

[ Hazard Codes ]:
T

[ Risk Phrases ]:
25

[ Safety Phrases ]:
45

[ RIDADR ]:
UN 2811 6.1 / PGIII

Articles

On the role of adenosine (A)₂A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats.

Psychopharmacol. Ser. 232(2) , 421-35, (2015)

Several studies have suggested the inhibitory control of adenosine (A)2A receptor stimulation in cocaine-induced behavioral actions.A combination of systemic or local drug injections and in vivo neuro...

Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1.

Neuropharmacology 72 , 197-203, (2013)

The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antips...

Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide.

Neuroscience 163(1) , 97-108, (2009)

Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction be...