A₃ Adenosine Receptors: Protective vs. Damaging Effects Identified Using Novel Agonists and Antagonists

Investigation of the physiologic role of the A₃ adenosine receptor has been facilitated by the availability of selective agonists and antagonists. Selective agonists include IB-MECA and the 2-chloro derivative Cl-IB-MECA. Selective antagonists have been identified and designed with the aid of molecular modeling among various nonpurine classes of heterocycles: flavonoids, 1,4-dihydropyridine derivatives, triazoloquinazolines, isoquinolines, and a triazolonaphthyridine. The dihydropyridine 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS 1191) is 1,300-fold selective for human A₃ (K_i of 31 nM) vs. A₁/A_2A adenosine receptors and also 28-fold A₃ selective in rat tissue (K_i of 1.42 mM). 9-Chloro-2-(2-furyl)-5-phenylacetylamino[1,2,4]-triazolo[1,5-c]quinazoline (MRS 1220) is useful as an A₃ selective antagonist only in human tissue, with a K_i value of 0.65 nM. The pyridine derivative 5-propyl 2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (MRS 1523) is a selective antagonist of both rat and human A₃ receptors, with K_i values of 113 and 19 nM, respectively. Paradoxical effects of A₃ agonists in the brain, heart and other tissues indicate that acute activation of A₃ receptors at greater than 10 mM concentrations acts as a lethal input to cells, whereas low, nanomolar concentrations of A₃ receptor agonists protect against apoptosis or ischemic damage. Adenosine A₃ receptor agonists, antagonists, or both, may be useful in treating inflammatory conditions.