Potent adenosine receptor antagonists that are selective for the A1 receptor subtype.

The xanthines currently represent the most potent class of adenosine receptor antagonists. However, known derivatives of xanthine show little difference in antagonist potency between the two putative adenosine receptor subtypes, A1 and A2. We conducted a systematic study of xanthine structure-activity relationships that compared antagonist potency at the A1 receptor of adipocytes with potency at the A2 receptor of platelets. Since adenosine receptors are coupled to adenylate cyclase in these tissues, inhibition of adenylate cyclase via A1 receptors and stimulation via A2 receptors were used as models of receptor activation. Antagonist potency was quantitated by Schild analysis, which yields an estimate of affinity (Ki) for the drug-receptor interaction. Ki values of a series of xanthine analogues enabled us to identify structural modifications than enhanced antagonist selectivity for one receptor subtype over the other. We found that changes in the substituent at position 8 of the xanthine nucleus influenced antagonist potency at the A1 adenosine receptor more than at the A2 receptor. In particular, an 8-cyclohexyl or 8-cyclopentyl substituent promoted antagonist selectivity for the A1 receptor subtype. Thus, 1,3-dipropyl-8-cyclopentylxanthine had comparatively high affinity (Ki = 0.47 +/- 2 nM) at the A1 receptor, and was roughly 150-fold more potent as an antagonist of the A1- than of the A2-adenosine receptor subtype. In addition, the cycloalkylxanthines were relatively ineffective as inhibitors of cyclic nucleotide phosphodiesterases when used at concentrations that produced marked adenosine receptor antagonism.