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In vitro pharmacological profile of the A2A receptor antagonist istradefylline

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Abstract

Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.

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Abbreviations

cAMP:

Cyclic adenosine monophosphate

C max :

Maximum concentration

CNS:

Central nervous system

COMT:

Catechol-O-methyl transferase

EC50 :

Concentration required for 50 % activity

GABA/ENK-MSN:

γ-Amino–butyric acid and enkephalin-containing medium spiny neuron

GPCR:

G protein-coupled receptor

GPe:

External segment of globus pallidus

IC50 :

Concentration required for 50 % inhibition

k +1 :

Association kinetic rate constant

k −1 :

Dissociation kinetic rate constant

K B :

Binding constant

K d :

Dissociation constant

K i :

Inhibition constant

k obs :

Observed binding kinetic rate constant

MAO:

Monoamine oxidase

PD:

Parkinson’s disease

PDE:

Phosphodiesterase

SNc:

Substantia nigra pars compacta

t 1/2 :

Half-life

References

  • Aoyama S, Kase H, Borrelli E (2000) Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J Neurosci 20(15):5848–5852

    PubMed  CAS  Google Scholar 

  • Armentero MT, Pinna A, Ferre S, Lanciego JL, Muller CE, Franco R (2011) Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 132(3):280–299

    Article  PubMed  CAS  Google Scholar 

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 14(1):48–58

    Article  PubMed  CAS  Google Scholar 

  • Augood SJ, Emson PC (1994) Adenosine A2a receptor mRNA is expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-expression study. Brain Res Mol Brain Res 22(1–4):204–210

    Article  PubMed  CAS  Google Scholar 

  • Bara-Jimenez W, Sherzai A, Dimitrova T, Favit A, Bibbiani F, Gillespie M, Morris MJ, Mouradian MM, Chase TN (2003) Adenosine A2A receptor antagonist treatment of Parkinson’s disease. Neurology 61(3):293–296

    Article  PubMed  CAS  Google Scholar 

  • Belardinelli L, Shryock JC, Ruble J, Monopoli A, Dionisotti S, Ongini E, Dennis DM, Baker SP (1996) Binding of the novel nonxanthine A2A adenosine receptor antagonist [3H]SCH58261 to coronary artery membranes. Circ Res 79(6):1153–1160

    Article  PubMed  CAS  Google Scholar 

  • Black KJ, Koller JM, Campbell MC, Gusnard DA, Bandak SI (2010) Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J Neurosci 30(48):16284–16292

    Article  PubMed  CAS  Google Scholar 

  • Boswell-Smith V, Spina D, Page CP (2006) Phosphodiesterase inhibitors. Br J Pharmacol 147(Suppl 1):S252–S257

    PubMed  CAS  Google Scholar 

  • Castagnoli N Jr, Petzer JP, Steyn S, Castagnoli K, Chen JF, Schwarzschild MA, Van der Schyf CJ (2003) Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists. Neurology 61(11 Suppl 6):S62–S68

    Article  PubMed  CAS  Google Scholar 

  • Ciruela F, Albergaria C, Soriano A, Cuffi L, Carbonell L, Sanchez S, Gandia J, Fernandez-Duenas V (2010) Adenosine receptors interacting proteins (ARIPs): behind the biology of adenosine signaling. Biochim Biophys Acta 1798(1):9–20

    Article  PubMed  CAS  Google Scholar 

  • DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13(7):281–285. Hayashi N, Kinemuchi H, Kamijo K (1981) Effect of tris (hydroxymethyl) aminomethane on amine oxidase activity in dog brain, liver and serum and in human placenta. Jpn J Pharmacol. 31(5):737–746.

    Google Scholar 

  • Hauser RA, Hubble JP, Truong DD, Istradefylline US-001 Study Group (2003) Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology 61(3):297–303

    Article  PubMed  CAS  Google Scholar 

  • Hayashi N, Kinemuchi H, Kamijo K. (1981) Effect of tris (hydroxymethyl) aminomethane on amine oxidase activity in dog brain, liver and serum and in human placenta. Jpn J Pharmacol. 31(5):737–46

    Google Scholar 

  • Hettinger BD, Lee A, Linden J, Rosin DL (2001) Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. J Comp Neurol 431(3):331–346

    Article  PubMed  CAS  Google Scholar 

  • Hide I, Padgett WL, Jacobson KA, Daly JW (1992) A2A adenosine receptors from rat striatum and rat pheochromocytoma PC12 cells: characterization with radioligand binding and by activation of adenylate cyclase. Mol Pharmacol 41(2):352–359

    PubMed  CAS  Google Scholar 

  • Hodgson RA, Bedard PJ, Varty GB, Kazdoba TM, Di Paolo T, Grzelak ME, Pond AJ, Hadjtahar A, Belanger N, Gregoire L, Dare A, Neustadt BR, Stamford AW, Hunter JC (2010) Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders. Exp Neurol 225(2):384–390

    Article  PubMed  CAS  Google Scholar 

  • Huynh T (2011) The Parkinson’s disease market. Nat Rev Drug Discov 10(8):571–572

    Article  PubMed  CAS  Google Scholar 

  • Jenner P (2005) Istradefylline, a novel adenosine A2A receptor antagonist, for the treatment of Parkinson’s disease. Expert Opin Investig Drugs 14(6):729–738

    Article  PubMed  CAS  Google Scholar 

  • Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF (2009) Adenosine, adenosine A2A antagonists, and Parkinson’s disease. Parkinsonism Relat Disord 15(6):406–413

    Article  PubMed  CAS  Google Scholar 

  • Kanda T, Jackson MJ, Smith LA, Pearce RK, Nakamura J, Kase H, Kuwana Y, Jenner P (1998) Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol 43(4):507–513

    Article  PubMed  CAS  Google Scholar 

  • Kanda T, Jackson MJ, Smith LA, Pearce RK, Nakamura J, Kase H, Kuwana Y, Jenner P (2000) Combined use of the adenosine A2A 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 162(2):321–327

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi S, Conforti L, Pun RY, Millhorn DE (1998) Adenosine modulates hypoxia-induced responses in rat PC12 cells via the A2A receptor. J Physiol 508(Pt 1):95–107

    PubMed  CAS  Google Scholar 

  • LeWitt PA, Guttman M, Tetrud JW, Tuite PJ, Mori A, Chaikin P, Sussman NM, 6002-US-005 Study Group (2008) Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 63(3):295–302

    Article  PubMed  CAS  Google Scholar 

  • Liu R, Guo X, Park Y, Huang X, Sinha R, Freedman ND, Hollenbeck AR, Blair A, Chen H (2012) Caffeine intake, smoking, and risk of Parkinson disease in men and women. Am J Epidemiol 175(11):1200–1207

    Article  PubMed  Google Scholar 

  • Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M, Japanese Istradefylline Study Group (2010) Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord 25(10):1437–1443

    Article  PubMed  Google Scholar 

  • Morelli M, Blandini F, Simola N, Hauser RA (2012) A2A receptor antagonism and dyskinesia in Parkinson’s disease. Park Dis 2012:1–8

    Article  Google Scholar 

  • Mori A, Shindou T (2003) Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists. Neurology 61(11 Suppl 6):S44–S48

    Article  PubMed  CAS  Google Scholar 

  • Neustadt BR, Hao J, Lindo N, Greenlee WJ, Stamford AW, Tulshian D, Ongini E, Hunter J, Monopoli A, Bertorelli R, Foster C, Arik L, Lachowicz J, Ng K, Feng KI (2007) Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. Bioorg Med Chem Lett 17(5):1376–1380

    Article  PubMed  CAS  Google Scholar 

  • Nikodejevic B, Senoh S, Daly JW, Creveling CR (1970) Catechol-O-methyltransferase. II. A new class of inhibitors of catechol-O-methyltransferase; 3,5-dihydroxy-4-methoxybenzoic acid and related compounds. J Pharmacol Exp Ther 174(1):83–93

    PubMed  CAS  Google Scholar 

  • Obeso JA, Rodriguez MC, DeLong MR (1997) Basal ganglia pathophysiology. Crit Review Adv Neurol 74:3–18

    CAS  Google Scholar 

  • Olah ME, Stiles GL (1995) Adenosine receptor subtypes: characterization and therapeutic regulation. Annu Rev Pharmacol Toxicol 35:581–606

    Article  PubMed  CAS  Google Scholar 

  • Olanow CW (2004) The scientific basis for the current treatment of Parkinson’s disease. Annu Rev Med 55:41–60

    Article  PubMed  CAS  Google Scholar 

  • Olanow CW, Koller WC (1998) An algorithm (decision tree) for the management of Parkinson’s disease: treatment guidelines. American Academy of Neurology. Neurology 50(3 Suppl 3):S1–S57

    Article  PubMed  CAS  Google Scholar 

  • Petzer JP, Steyn S, Castagnoli KP, Chen JF, Schwarzschild MA, Van der Schyf CJ, Castagnoli N (2003) Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorg Med Chem 11(7):1299–1310

    Article  PubMed  CAS  Google Scholar 

  • Pollack AE, Harrison MB, Wooten GF, Fink JS (1993) Differential localization of A2a adenosine receptor mRNA with D1 and D2 dopamine receptor mRNA in striatal output pathways following a selective lesion of striatonigral neurons. Brain Res 631(1):161–166

    Article  PubMed  CAS  Google Scholar 

  • Postuma RB, Lang AE, Munhoz RP, Charland K, Pelletier A, Moscovich M, Filla L, Zanatta D, Rios Romenets S, Altman R, Chuang R, Shah B (2012) Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology 79(7):651–658

    Article  PubMed  CAS  Google Scholar 

  • Sebastiao AM, Ribeiro JA (2000) Fine-tuning neuromodulation by adenosine. Trends Pharmacol Sci 21(9):341–346

    Article  PubMed  CAS  Google Scholar 

  • Shimada J, Suzuki F, Nonaka H, Ishii A, Ichikawa S (1992) (E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists. J Med Chem 35(12):2342–2345

    Article  PubMed  CAS  Google Scholar 

  • Shimada J, Koike N, Nonaka H, Shiozaki S, Yanagawa K, Kanda T, Kobayashi H, Ichimura M, Nakamura J, Kase H, Suzuki F (1997) Adenosine A2A antagonists with potent anti-cataleptic activity. Bioorg Med Chem Lett 7(18):2349–2352

    Article  CAS  Google Scholar 

  • Shiozaki S, Ichikawa S, Nakamura J, Kitamura S, Yamada K, Kuwana Y (1999) Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP. Psychopharmacology (Berlin) 147(1):90–95

    Article  CAS  Google Scholar 

  • Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P, Sussman NM (2008) A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 70(23):2233–2240

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Sales and Marketing Division, Marketing Department, Kyowa Hakko Kirin Co., Ltd., 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo, 100-8185, Japan

    Mayumi Saki

  2. Development Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan

    Koji Yamada & Tomoyuki Kanda

  3. Discovery and Development Research Promotion Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan

    Etsuko Koshimura

  4. Biologics Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo, 194-8533, Japan

    Katsutoshi Sasaki

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  1. Mayumi Saki
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  2. Koji Yamada
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  3. Etsuko Koshimura
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  4. Katsutoshi Sasaki
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  5. Tomoyuki Kanda
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Correspondence to Tomoyuki Kanda.

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Saki, M., Yamada, K., Koshimura, E. et al. In vitro pharmacological profile of the A2A receptor antagonist istradefylline. Naunyn-Schmiedeberg's Arch Pharmacol 386, 963–972 (2013). https://doi.org/10.1007/s00210-013-0897-5

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