A novel class of adenosine A3 receptor ligands.: 2.: Structure affinity profile of a series of isoquinoline and quinazoline compounds

1-Substituted 3-(2-pyridinyl)isoquinolines have been shown to form a novel class of adenosine AS receptor ligands. In the present study further investigations of this never lead and the structure affinity relationships of this class of compounds are described. First, the influence of an amide group at position 1 of the isoquinoline ring on the adenosine A(3) receptor affinity was determined. A carboxamide proved to be a useful spacer between the isoquinoline and a phenyl ring. N-[2-(2-pyridinyl)isoquinolin-4-yl]benzamide (VUF8507, compound 6) had an affinity of 200 nM at the adenosine A(3) receptor. Second, we investigated the effects of substitution of the benzamide ring of 6 with a series of mono- and disubstituted N-[3-(2-pyridinyl)isoquinoline]benzamides. The ratio of the tautomers of the benzamides was determined in the solid state and in solution by spectroscopic techniques (IR and NMR). Affinities were determined in radioligand binding assays at rat brain A(1) and A(2A) receptors and at cloned human A(3) receptor. The benzamides showed higher adenosine A(3) receptor affinity than aliphatic amides. We propose that the adenosine A(3) receptor affinity of the different benzamides is related to their presence in either the iminol or amide form. Ligands present in the iminol form showed relatively high adenosine A(3) receptor affinity. Finally, we explored the influence of replacement of C-4 of the isoquinoline ring by a nitrogen atom. Comparison of isoquinolines with the corresponding quinazolines revealed that both compounds showed similar adenosine A(3) receptor affinity. These investigations led to potent and selective human adenosine A(3) receptor ligands with affinities in the nanomolar range. The subtype-selective compound 4-methoxy-N-[2-(2-pyridinyl)quinazolin-4-yl]benzamide (VUF8504, 13) with an affinity of 17.0 nM at the human adenosine A(3) receptor might become a useful tool in the pharmacological characterization or the investigation of the physiological function pf this receptor.