The adenosine A 2A receptor is considered to be an important target for the development of new therapies for Parkinson’s disease. Several antagonists of the A 2A receptor have entered clinical trials for this purpose and many research groups have initiated programs to develop A 2A receptor antagonists. Most A 2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A 2A receptor antagonists and to further explore the structure–activity relationships (SARs) of A 2A antagonism by the xanthine class of compounds, this study examines the A 2A 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 K i value of 11.9nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats, providing evidence that it is in fact an A 2A 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 A 2A receptor.