A NOVEL CLASS OF ADENOSINE A(3) 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 n ovel class of adenosine AS receptor ligands. In the present study furt her investigations of this never lead and the structure affinity relat ionships of this class of compounds are described. First, the influenc e of an amide group at position 1 of the isoquinoline ring on the aden osine A(3) receptor affinity was determined. A carboxamide proved to b e a useful spacer between the isoquinoline and a phenyl ring. N-[2-(2- pyridinyl)isoquinolin-4-yl]benzamide (VUF8507, compound 6) had an affi nity 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 sol id state and in solution by spectroscopic techniques (IR and NMR). Aff inities were determined in radioligand binding assays at rat brain A(1 ) and A(2A) receptors and at cloned human A(3) receptor. The benzamide s showed higher adenosine A(3) receptor affinity than aliphatic amides . We propose that the adenosine A(3) receptor affinity of the differen t benzamides is related to their presence in either the iminol or amid e form. Ligands present in the iminol form showed relatively high aden osine A(3) receptor affinity. Finally, we explored the influence of re placement of C-4 of the isoquinoline ring by a nitrogen atom. Comparis on 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) recept or ligands with affinities in the nanomolar range. The subtype-selecti ve compound ethoxy-N-[2-(2-pyridinyl)quinazolin-4-yl]benzamide (VUF850 4, 13) with an affinity of 17.0 nM at the human adenosine A(3) recepto r might become a useful tool in the pharmacological characterization o r the investigation of the physiological function pf this receptor.