DERIVATIVES OF THE TRIAZOLOQUINAZOLINE ADENOSINE ANTAGONIST (CGS-15943) HAVING HIGH POTENCY AT THE HUMAN A(2B) AND A(3) RECEPTOR SUBTYPES

The adenosine antagonist 2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5- amine (CGS 15943) binds nonselectively to human A(1), A(2A), and A(3) receptors with high affinity. Acylated derivatives and one alkyl deriv ative of the 5-amino group and other modifications were prepared in an effort to enhance A(2B) or A(3) subtype potency. In general, distal m odifications of the N-5-substituent were highly modulatory to potency and selectivity at adenosine receptors, as determined in radioligand b inding assays at rat brain A(1) and A(2A) receptors and at recombinant human A(3) receptors. In Chinese hamster ovary cells stably transfect ed with human A(2B) receptor cDNA, inhibition of agonist-induced cycli c AMP production was measured. An N-5-(2-iodophenyl)acetyl derivative was highly selective for A(2A) receptors. An (R)-N-5-alpha-methyl-(phe nylacetyl) derivative was the most potent derivative at A(3) receptors , with a K-i value of 0.36 nM. A bulky N-5-diphenylacetyl derivative, 13, displayed a K-i value of 0.59 nM at human A(3) receptors and was m oderately selective for that subtype. Thus, a large, nondiscriminating hydrophobic region occurs in the Ag receptor in proximity to the N-5- substituent. A series of straight-chain N-5-aminoalkylacyl derivatives demonstrated that for A(2B) receptors the optimal chain length occurs with three methylene groups, i.e., the N-5-gamma-aminobutyryl derivat ive 27 which had a pA(2) value of 8.0 but was not selective for A(2B) receptors. At A(1), A(2A), and A(3) receptors however the optimum occu rs with four methylene groups. An N-5-pivaloyl derivative, which was l ess potent than 27 at A(1), A(2A), and A(3) receptors, retained modera te potency at A(2B) receptors. A molecular model of the 27-A(2B) recep tor complex based on the structure of rhodopsin utilizing a ''cross-do cking'' procedure was developed in order to visualize the environment of the ligand binding site.