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The adenosine A(2A) antagonistic properties of selected C8-substituted xanthines.
Bioorg Chem. 2013 Aug; 49:49-58.BC

Abstract

The adenosine A2A receptor is considered to be an important target for the development of new therapies for Parkinson's disease. Several antagonists of the A2A receptor have entered clinical trials for this purpose and many research groups have initiated programs to develop A2A receptor antagonists. Most A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists and to further explore the structure-activity relationships (SARs) of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthines, 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines. The results document that among these series, the (E)-8-styrylxanthines have the highest binding affinities with the most potent homologue, (E)-1,3-diethyl-7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats, providing evidence that it is in fact an A2A receptor antagonist. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor.

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Authors+Show Affiliations

Van der Walt MM
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Terre'Blanche G
No affiliation info available
Petzer A
No affiliation info available
Lourens AC
No affiliation info available
Petzer JP
No affiliation info available

MeSH

Adenosine A2 Receptor AntagonistsDose-Response Relationship, DrugEnzyme InhibitorsHumansMolecular StructureMonoamine OxidaseReceptor, Adenosine A2ARecombinant ProteinsStructure-Activity RelationshipXanthines

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23892098

Citation

Van der Walt, Mietha M., et al. "The Adenosine A(2A) Antagonistic Properties of Selected C8-substituted Xanthines." Bioorganic Chemistry, vol. 49, 2013, pp. 49-58.
Van der Walt MM, Terre'Blanche G, Petzer A, et al. The adenosine A(2A) antagonistic properties of selected C8-substituted xanthines. Bioorg Chem. 2013;49:49-58.
Van der Walt, M. M., Terre'Blanche, G., Petzer, A., Lourens, A. C., & Petzer, J. P. (2013). The adenosine A(2A) antagonistic properties of selected C8-substituted xanthines. Bioorganic Chemistry, 49, 49-58. https://doi.org/10.1016/j.bioorg.2013.06.006
Van der Walt MM, et al. The Adenosine A(2A) Antagonistic Properties of Selected C8-substituted Xanthines. Bioorg Chem. 2013;49:49-58. PubMed PMID: 23892098.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The adenosine A(2A) antagonistic properties of selected C8-substituted xanthines. AU - Van der Walt,Mietha M, AU - Terre'Blanche,Gisella, AU - Petzer,Anél, AU - Lourens,Anna C U, AU - Petzer,Jacobus P, Y1 - 2013/07/04/ PY - 2012/12/18/received PY - 2013/05/13/revised PY - 2013/06/17/accepted PY - 2013/7/30/entrez PY - 2013/7/31/pubmed PY - 2016/3/2/medline KW - (E)-8-(3-chlorostyryl)caffeine KW - 1,3-[(3)H]-dipropyl-8-cyclopentylxanthine KW - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine KW - Adenosine A(2A) receptors KW - Antagonism KW - CNS KW - CPA KW - CSC KW - DMF KW - DMSO KW - EDAC KW - GPCR KW - Haloperidol-induced catalepsy KW - MAO-B KW - MPTP KW - N,N-dimethylformamide KW - N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide KW - N-[(3)H]ethyladenosin-5′-uronamide KW - Parkinson’s disease KW - SAR KW - SI KW - Xanthine KW - [(3)H]DPCPX KW - [(3)H]NECA KW - central nervous system KW - cyclopentyladenosine KW - dimethyl sulfoxide KW - guanine nucleotide-binding protein (G protein)-coupled receptor KW - monoamine oxidase B KW - selectivity index KW - structure–activity relationship SP - 49 EP - 58 JF - Bioorganic chemistry JO - Bioorg Chem VL - 49 N2 - The adenosine A2A receptor is considered to be an important target for the development of new therapies for Parkinson's disease. Several antagonists of the A2A receptor have entered clinical trials for this purpose and many research groups have initiated programs to develop A2A receptor antagonists. Most A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists and to further explore the structure-activity relationships (SARs) of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthines, 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines. The results document that among these series, the (E)-8-styrylxanthines have the highest binding affinities with the most potent homologue, (E)-1,3-diethyl-7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats, providing evidence that it is in fact an A2A receptor antagonist. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/23892098/The_adenosine_A_2A__antagonistic_properties_of_selected_C8_substituted_xanthines_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(13)00023-0 DB - PRIME DP - Unbound Medicine ER -