KF17837 ((E)-8-(3,4-DIMETHOXYSTYRYL)-1,3-DIPROPYL-7-METHYLXANTHINE), A POTENT AND SELECTIVE ADENOSINE A(2) RECEPTOR ANTAGONIST

8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine exhibited high affinity and selectivity for adenosine A(2A) receptors in binding assay using rat striatal A(2A) receptors labeled with [H-3]2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). The affinity was stereo selective: the E isomer, KF17837, showed a K-i value of 1.0 +/- 0.057 nM for the A(2A) receptors, whereas the Z isomer showed much lower affinity. KF17837 had 62-fold selectivity for the A(2A) receptors versus rat forebrain A(1) receptors labeled with [H-3]N-6-cyclohexyladenosine (CHA). KF17837 was rapidly photoisomerized to form a stable equilibrium mixture (18% E - 82% Z), KF17837S, which showed K-i values of 7.9 +/- 0.055 nM and 390 +/- 68 nM for the A(2A) and A(1) receptors, respectively. The inhibition type was competitive for [3H]CGS21680 binding. In rat pheochromocytoma PC12 cells KF17837S antagonized cAMP accumulation induced by 1 mu M CGS21680 via the A(2A) receptors, with an IC50 value of 53 +/- 10 nM. cAMP accumulation induced by 10 mu M 5'-N-ethylcarboxamidoadenosine via the A(2B) receptors in Jurkat cells (human T-cell line) was inhibited by KF17837S with an IC50 value of 1500 +/- 290 nM. These results indicate that KF17837S (and hence KF17837) is a highly potent and selective adenosine A(2A) receptor antagonist.