title: The adenosine A(2A) antagonistic properties of selected C8-substituted xanthines.
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.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Mietha M
authors.initials: MM
authors.lastname: Van der Walt
authors.forename: Gisella
authors.initials: G
authors.lastname: Terre'Blanche
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.forename: Anna C U
authors.initials: AC
authors.lastname: Lourens
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D004791:Enzyme Inhibitors; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins; D014970:Xanthines; D008995:Monoamine Oxidase
keywords: (E)-8-(3-chlorostyryl)caffeine; 1,3-[(3)H]-dipropyl-8-cyclopentylxanthine; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenosine A(2A) receptors; Antagonism; CNS; CPA; CSC; DMF; DMSO; EDAC; GPCR; Haloperidol-induced catalepsy; MAO-B; MPTP; N,N-dimethylformamide; N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; N-[(3)H]ethyladenosin-5′-uronamide; Parkinson’s disease; SAR; SI; Xanthine; [(3)H]DPCPX; [(3)H]NECA; central nervous system; cyclopentyladenosine; dimethyl sulfoxide; guanine nucleotide-binding protein (G protein)-coupled receptor; monoamine oxidase B; selectivity index; structure–activity relationship