On the basis of a model we recently developed for the antagonist binding site of the adenosine A1 receptor (J. Med. Chem. 1990, 33, 1708-1713), it was predicted that 1H-imidazo[4,5-c]quinolin-4-amines would be antagonists of the A1 receptor. Furthermore, it was expected that certain hydrophobic substitutions at the 2- and 4-positions would enhance affinity. Here, we report on the synthesis and the adenosine A1 and A2 receptor affinity of substituted 1H-imidazo[4,5-c]quinolin-4-amines. Some of these compounds have nanomolar affinity for the A1 receptor. The structure-activity relationships (SAR) of these compounds are discussed in relation to SAR for other adenosine receptor ligands. The 1H-imidazo[4,5-c]quinolin-4-amines constitute a novel class of non-xanthine adenosine antagonists.