Autoradiographic comparison of the potency of several structurally unrelated adenosine receptor antagonists at adenosine A1 and A(2A) receptors.

We have examined the potency of several adenosine receptor antagonists at adenosine A1 and A2A receptors using quantitative autoradiography and have compared the results with those of previous studies using the same radioligands in membrane preparations. The agonists [3H]cyclohexyladenosine and [3H]2-[p-(2-carbonylethyl)-phenylethylamino]-5'-N-ethylcarbo xamido adenosine ([3H]CGS 21680) were used as radioligands for the two receptors. The results show that 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX) is almost 1000-fold and 8-chloro-4-cyclohexyl-amino-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a] quinoxaline (CP-68,247) about 300-fold more potent at adenosine A1 receptors in cortex and striatum than at striatal adenosine A2A receptors. Conversely, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine (SCH 58261) is approximately 1000-fold and 4-(2-[7-amino-2-(2-furyl) [1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol (ZM 241,385) about 400-fold more potent at adenosine A2A than at A1 receptors. Caffeine and its metabolites did not show any selectivity. Other studied antagonists were non-selective or showed a modest (20- to 40-fold) adenosine A2A receptor selectivity. Thus, only a few of the antagonists show such high selectivity that it is not offset by differences in drug distribution and levels of receptor subtype expression.