Derivatives of the triazoloquinazoline adenosine antagonist (CGS15943) are selective for the human A(3) receptor subtype

The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) binds to human A(3) receptors with high affinity (K-i = 14 nM), while it lacks affinity at rat A(3) receptors. Acylated derivatives of the 5-amino group and other modifications were prepared in an effort to provide A(3) subtype selectivity. Affinity was determined in radioligand binding assays at rat brain A(1) and A(2A) receptors using [H-3]-(R)-PIA ([H-3]-(R)-N-6-(phenylisopropyl)adenosine) and [H-3]CGS 21680 ([H-3]-2-[[4-(2-carboxy ethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl)adenosine), respectively. Affinity was determined at cloned human A(3) receptors using [I-125]AB-MECA (N-6-(4-amino-3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine). A series of straight chain alkyl amides demonstrated that the optimal chain length occurs with the 5-N-propionyl derivative, 3, which had a K-i value of 7.7 nM at human A(3) receptors, and was 40- and 14-fold selective vs rat A(1) and A(2A) receptors, respectively. The 5-N-benzoyl derivative, 10, displayed K-i values of 680 and 273 nM at rat A(1) and A(2A) receptors, respectively, and 3.0 nM at human A(3) receptors. A 5-N-phenylacetyl derivative, 12, was 470-fold selective for human A(3) VS rat Al receptors with a K-i value of 0.65 nM. A conjugate of Boc-gamma-aminobutyric acid was also prepared but was nonselective. Conversion of the 5-amino group of CGS15943 to an oxo function resulted in lower affinity but 15-fold selectivity for human A(3) receptors.