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 (Ki of 31 nM) vs. A1/A2A adenosine receptors and also 28-fold A3 selective in rat tissue (Ki 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 Ki 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 Ki 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.