A new generation of adenosine receptor antagonists: From di- to trisubstituted aminopyrimidines Original Research Article

New adenosine receptor ligands were designed as hybrid structures between previously synthesized substituted dicyanopyridines and aminopyrimidines, yielding two series of cyano-substituted diphenylaminopyrimidines. We were interested in assessing the effect of this substitution pattern on both affinity and intrinsic activity, as the dicyanopyridines comprised both agonists and inverse agonists, whereas the original aminopyrimidines were exclusively inverse agonists. It was found that the new compounds were generally selective for adenosine A1 receptors, although affinity for the adenosine A2A receptor was also noticed for some of the compounds. In a cAMP second messenger assay the compounds behaved as inverse agonists rather than agonists. Among the more A1 receptor-selective compounds were 5 (LUF6048), 27 (LUF6040) and 53 (LUF6056) with Ki values of 8.1, 1.2 and 5.7 nM, respectively.