Characterization of the Potency, Selectivity, and Pharmacokinetic Profile for Six Adenosine A2A Receptor Antagonists

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2007 Feb 21

PMID 17310264

Citations 33

Authors

Ming Yang

Daniel Soohoo

Sandriyana Soelaiman

Rao Kalla

Jeff Zablocki

Nancy Chu

Kwan Leung

Lina Yao

Ivan Diamond

Luiz Belardinelli

John C Shryock

Affiliations

Soon will be listed here.

Abstract

Antagonists of adenosine A2A receptors (A2A -antagonists) with different chemical structures have been developed by several pharmaceutical companies for the potential treatment of Parkinson's disease. Pharmacological characterization of these antagonists was incomplete, and different assay conditions were used in different labs. Therefore, we characterized the potencies, selectivities, and pharmacokinetic profiles of six prototypical A2A -antagonists. Displacements of [3H]MSX-2 and of [3H]CGS21680 binding to the human cloned and rat A2A receptors were performed. The rank order of potency of antagonists to displace [(3)H]MSX-2 binding to the human A2A was SCH58261 > or = Biogen-34 > or = Ver-6623 > or = MSX-2 > KW-6002 > > DMPX. For the rat striatal A2A, the order of potency was Biogen-34 > or = SCH58261 > or = Ver-6623 > or = MSX-2 > or = KW-6002 > > DMPX. SCH58261 was the most potent antagonist of the human A2A with a K(i) value of 4 nM, whereas Biogen-34 was the most potent antagonist of the rat A2A with a K(i) value of 1.2 nM. Similar results were obtained from cAMP assays. Selectivities of A2A-antagonists were determined using radioligands [3H]DPCPX, [3H]ZM241385, and [125I]-AB-MECA for A1, A2B, and A3 receptors, respectively. KW-6002 and Biogen-34 exhibited the highest selectivity for A2A vs A1 (human and rat), respectively. The pharmacokinetic profiles of antagonists were evaluated in vivo in rats. DMPX and KW-6002 had the greatest oral bioavailability. In contrast, SCH58261, MSX-2, and Ver-6623 had low or poor oral bioavailability. In summary, SCH58261, Biogen-34, MSX-2, and Ver-6623 had high affinities for both human and rat A2A receptors, with reasonable selectivity for A2A over A1 and A2B receptors. They are suitable as A2A -antagonists for in vitro pharmacological studies. Among the six A2A-antagonists, KW-6002 is the best for use in in vivo animal studies, particularly for a CNS target, based on its bioavailability, half life, and brain penetration.

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References

Sauer R, Maurinsh J, Reith U, FULLE F, Klotz K, Muller C . Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A(2A)-selective adenosine receptor antagonists. J Med Chem. 2000; 43(3):440-8. DOI: 10.1021/jm9911480. View

Weiss S, Benwell K, Cliffe I, Gillespie R, Knight A, Lerpiniere J . Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease. Neurology. 2003; 61(11 Suppl 6):S101-6. DOI: 10.1212/01.wnl.0000095581.20961.7d. View

Zocchi C, Ongini E, Conti A, Monopoli A, Negretti A, Baraldi P . The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist. J Pharmacol Exp Ther. 1996; 276(2):398-404. View

Muller C, Sandoval-Ramirez J, Schobert U, Geis U, Frobenius W, Klotz K . 8-(Sulfostyryl)xanthines: water-soluble A2A-selective adenosine receptor antagonists. Bioorg Med Chem. 1998; 6(6):707-19. DOI: 10.1016/s0968-0896(98)00025-x. View

Vu C, Peng B, Kumaravel G, Smits G, Jin X, Phadke D . Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists. J Med Chem. 2004; 47(17):4291-9. DOI: 10.1021/jm0498405. View

Knutsen L, Weiss S . KW-6002 (Kyowa Hakko Kogyo). Curr Opin Investig Drugs. 2001; 2(5):668-73. View

Ralevic V, Burnstock G . Receptors for purines and pyrimidines. Pharmacol Rev. 1998; 50(3):413-92. View

Ongini E, Monopoli A, Cacciari B, Baraldi P . Selective adenosine A2A receptor antagonists. Farmaco. 2001; 56(1-2):87-90. DOI: 10.1016/s0014-827x(01)01024-2. View

Olah M, Jacobson K, Stiles G . 125I-4-aminobenzyl-5'-N-methylcarboxamidoadenosine, a high affinity radioligand for the rat A3 adenosine receptor. Mol Pharmacol. 1994; 45(5):978-82. PMC: 5553074. View

10.

Klotz K . Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch Pharmacol. 2000; 362(4-5):382-91. DOI: 10.1007/s002100000315. View

11.

Hockemeyer J, Burbiel J, Muller C . Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson's disease. J Org Chem. 2004; 69(10):3308-18. DOI: 10.1021/jo0358574. View

12.

Aoyama S, Koga K, Mori A, Miyaji H, Sekine S, Kase H . Distribution of adenosine A(2A) receptor antagonist KW-6002 and its effect on gene expression in the rat brain. Brain Res. 2002; 953(1-2):119-25. DOI: 10.1016/s0006-8993(02)03277-8. View

13.

Daly J, Padgett W, Shamim M . Analogues of 1,3-dipropyl-8-phenylxanthine: enhancement of selectivity at A1-adenosine receptors by aryl substituents. J Med Chem. 1986; 29(8):1520-4. DOI: 10.1021/jm00158a034. View

14.

Vu C, Pan D, Peng B, Sha L, Kumaravel G, Jin X . Studies on adenosine A2a receptor antagonists: comparison of three core heterocycles. Bioorg Med Chem Lett. 2004; 14(19):4831-4. DOI: 10.1016/j.bmcl.2004.07.047. View

15.

Kull B, Arslan G, Nilsson C, Owman C, Lorenzen A, Schwabe U . Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors. Biochem Pharmacol. 1999; 57(1):65-75. DOI: 10.1016/s0006-2952(98)00298-6. View

16.

Jiang Q, Van Rhee A, Kim J, Yehle S, Wess J, Jacobson K . Hydrophilic side chains in the third and seventh transmembrane helical domains of human A2A adenosine receptors are required for ligand recognition. Mol Pharmacol. 1996; 50(3):512-21. PMC: 3418326. View

17.

Cacciari B, Pastorin G, Spalluto G . Medicinal chemistry of A2A adenosine receptor antagonists. Curr Top Med Chem. 2003; 3(4):403-11. DOI: 10.2174/1568026033392183. View

18.

Dionisotti S, Ongini E, Zocchi C, Kull B, Arslan G, Fredholm B . Characterization of human A2A adenosine receptors with the antagonist radioligand [3H]-SCH 58261. Br J Pharmacol. 1997; 121(3):353-60. PMC: 1564691. DOI: 10.1038/sj.bjp.0701119. View

19.

Merighi S, Varani K, Gessi S, Cattabriga E, Iannotta V, Ulouglu C . Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line. Br J Pharmacol. 2001; 134(6):1215-26. PMC: 1573044. DOI: 10.1038/sj.bjp.0704352. View

20.

Hauber W, Nagel J, Sauer R, Muller C . Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen. Neuroreport. 1998; 9(8):1803-6. DOI: 10.1097/00001756-199806010-00024. View