A3 adenosine receptors: Protective vs. damaging effects identified using novel agonists and antagonists
✍ Scribed by Kenneth A. Jacobson; Stefano Moro; Yong-Chul Kim; An-Hu Li
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 298 KB
- Volume
- 45
- Category
- Article
- ISSN
- 0272-4391
No coin nor oath required. For personal study only.
✦ Synopsis
Investigation of the physiologic role of the A 3 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 2methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS 1191) is 1,300-fold selective for human A 3 (K i of 31 nM) vs. A 1 /A 2A adenosine receptors and also 28-fold A 3 selective in rat tissue (K i of 1.42 µM). 9-Chloro-2-(2-furyl)-5-phenylacetylamino[1,2,4]-triazolo[1,5-c]quinazoline (MRS 1220) is useful as an A 3 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 A 3 receptors, with K i values of 113 and 19 nM, respectively. Paradoxical effects of A 3 agonists in the brain, heart and other tissues indicate that acute activation of A 3 receptors at greater than 10 µM concentrations acts as a lethal input to cells, whereas low, nanomolar concentrations of A 3 receptor agonists protect against apoptosis or ischemic damage. Adenosine A 3 receptor agonists, antagonists, or both, may be useful in treating inflammatory conditions.