PD 115,199: an antagonist ligand for adenosine A2 receptors

PD 115,199, N-[2-(dimethylamino)ethyl]-N-methyl-4-[(2,3,6,-7-tetrahydro)-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl]benzenesulfonamide, is an adenosine (ado) antagonist with high affinity at both the A1 and A2 subtypes of ado receptor, with an IC50 of 24 nM in [3H]CHA binding to A1 receptors and 23 nM in [3H]NECA binding to A2 receptors. [3H]PD 115,199 (126 Ci/mmol) was prepared by reduction of the diallyl analog. In rat striatal membranes, dose-inhibition curves for the A1-selective ado antagonist PD 116,948 vs 0.5 nM [3H]PD 115,199 were markedly biphasic, with 21% of specific binding representing A1 sites with an IC50 for PD 116,948 of 0.52 nM, and the remaining 79% representing apparent A2 sites with an IC50 for PD 116,948 of 163 nM. Subsequent experiments were done in the presence of 20 nM PD 116,948 to eliminate A1 binding. Under these conditions, about 80% of binding was specific. [3H]PD 115,199 bound with high affinity (K/sub d/ 10 nM) to a limited number of sites (Bmax 120 pmol/g wet weight). Affinities of compounds in [3H]PD 115,199 binding closely paralleled their affinities in [3H]NECA binding. Ado antagonists were generally several fold more active vs [3H]PD 115,199 than vs [3H]NECA, whereas the reverse was the case for agonists. Binding was much higher in striatum than in other brain areas. These results indicate that [3H]PD 115,199 binds to a high-affinity A2 receptor