SCH 58261: A selective A2A adenosine receptor antagonists

The recent discovery of selective antagonists for the A_2A adenosine receptors has been of great help to further research in this field. One compound, SCH 58261, 5- amino-7-(β-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, is playing a key part in a variety of studies. This review describes its pharmacological characteristics as they are emerging in various laboratories. The compound has an affinity in the low nM range (Ki value of 1–2 nM) for A_2A receptors located on membranes from a variety of tissues and cell types, including rat and bovine brain striatum, human platelets, lymphocytes and neutrophils, porcine coronary arteries, and CHO cells transfected with the cloned human A_2A receptors. SCH 58261 has little or no affinity up to the μM range for adenosine A_2B, A₃, or other G protein-coupled receptors. Selectivity for A_2A vs. A₁ receptors varies from 53- to 750-fold, depending on membranes or type of assay. SCH 58261 blocks A_2A-receptor mediated increase of cyclic AMP formation with high potency (e.g., IC₅₀ values between 15 and 20 nM in human white blood cells). The tritiated form of SCH 58261 specifically labels A_2A receptors in discrete regions of the rat brain such as caudate-putamen, nucleus accumbens, and tuberculum olfactorium. In classic in vitro bioassays, such as A_2A-receptor-mediated vasodilation in coronary arteries, SCH 58261 displays competitive antagonistic properties (e.g., pA₂ value of 9.5 in porcine coronary arteries). In assays involving responses mediated by A₁ or A_2B receptors, SCH 58261 shows little or no activity up to concentrations about 100-fold higher than those affecting A_2A receptors (higher concentrations not being testable due to its poor water solubility). In the rat, SCH 58261 enhances locomotor activity (at 3.7 mg/kg ip), increases wakefulness (10 mg/kg ip) and slightly increases both blood pressure and heart rate (10 mg/kg ip). These activities appear to be specifically mediated by A_2A receptors since the drug counteracts the effect of A_2A receptor agonists in some experimental paradigms. In models mimicking CNS disorders, SCH 58261 potentiates the activity of L-DOPA or dopamine receptor agonists in the 6-hydroxydopamine-lesioned rat model. Moreover, the compound reduces brain infarct size in a rat model of cerebral ischemia. Altogether, SCH 58261 and its radiolabeled form have emerged as interesting tools for better understanding the function of A_2A receptors in physiological or altered conditions. Moreover, the neuroprotective properties of SCH 58261 indicate that drugs of this class have a potential for treatment of brain damage produced by Parkinson's disease or stroke. Drug Dev. Res. 42:63–70, 1997. © 1997 Wiley-Liss, Inc.