Autoradiographic comparison of the potency of several structurally unrelated adenosine receptor antagonists at adenosine A1 and A2A receptors

We have examined the potency of several adenosine receptor antagonists at adenosine A(1) and A(2), receptors using quantitative autoradiography and have compared the results with those of previous studies using the same radioligands in membrane preparations. The agonists [H-3]cyclohexyladenosine and [H-3]2-[p-(2-carbonylethyl)-phenylethylamino]-5'-N-ethylcarboxamido adenosine ([H-3]CGS 21680) were used as radioligands for the two receptors. The results sinew 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 A(2A) receptors in cortex and striatum than at striatal adenosine A(2A) 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 A(2A) than at A(1) 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 A(2A) 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. (C) 1999 Elsevier Science B.V. All rights reserved.