Adenosine receptors are localized virtually in all tissues and modulate a wide range of physiological functions, divided into A1 and A2 subtypes which can be distinguished by adenosine agonist structure-activity relationships and have opposite effects on adenylate cyclase. The methylxanthines theophylline and caffeine exhibit pharmacological actions primarily through adenosine receptor blockade but are virtually nonselective and have weak affinity for A1 and A2 receptors. While selective A1 antagonists have been developed, no antagonist with high selectivity toward the A2 receptor has been forthcoming. This study describes a series of (E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthine derivatives containing a new hydrophobic moiety at the 8-position as potent and selective adenosine A2 antagonists. The potency of these xanthine derivatives at adenosine A1 and A2 receptors was determined by standard radioligand binding procedures: A1 binding was performed with N6-[3H]cyclohexyladenosine in guinea pig forebrain membranes, and A2 binding with N-[3H]ethyladenosin-5'-uronamide in rat striatal membranes. Results showed that (E)-styryl substitution at the 8-position (e.g., compound 10) enhanced A2 affinity and selectivity (A1 Ki 1800 nM, A2 Ki 26 nM, selectivity ratio 69). 7-Methyl substitution generally increased A2 selectivity (e.g., compound 24, a 7-methyl derivative of 8-(3,4,5-trimethoxystyryl)xanthine, had higher selectivity than its 7-H counterpart). 3,4,5-Trimethoxystyryl substitution at the 8-position further improved A2 affinity, and alkyl substitution at the 1- and 3-positions was important for A2 receptor affinity. These derivatives represent potent and selective adenosine A2 antagonists.