Carola Gallo-Rodriguez

8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonist in vitro and in vivo

An adenosine antagonist, 8‐(3‐chlorostyryl)caffeine (CSC), was shown previously to be 520‐fold selective for A2a‐adenosine receptors in radioligand binding assays in the rat brain. In reversing agonist effects on adenylate cyclase, CSC was 22‐fold selective for A2a receptors in rat pheochromocytoma cells (K b 60 nM) vs. A1 receptors in rat adipocytes (K b 1.3 μM). Administered i.p. in NIH mice at a dose of 1 mg/kg, CSC shifted the curve for locomotor depression elicited by the A2a‐selective agonist APEC to the right (ED50 value for APEC shifted from 20 μg/kg i.p. to 190 μg/kg). CSC had no effect on locomotor depression elicited by an ED50 dose of the A1‐selective agonist CHA. CSC alone at a dose of 5 mg/kg stimulated locomotor activity by 22% over control values. Coadministration of CSC and the A1‐selective antagonist CPX, both at non‐stimulatory doses, increased activity by 37% (P < 0.001) over CSC alone, suggesting a behavioral synergism of A1‐ and A2‐antagonist effects in the CNS.

A role for central A3-adenosine receptors. Mediation of behavioral depressant effects.

The behavioral effects of a selective A3 adenosine receptor agonist 3‐IB‐MECA (N 6‐(3‐iodobenzyl)‐5‐N‐methylcarboxamidoadenosine) in mice and the localization of radioligand binding sites in mouse brain were examined. Low levels of A3 adenosine receptors were detected in various regions of the mouse brain (hippocampus, cortex, cerebellum, striatum), using a radioiodinated, high‐affinity A3‐agonist radioligand [125I]AB‐MECA (N 6‐(3‐iodo‐4‐aminobenzyl)‐5‐N‐methylcarboxamidoadenosine). Scatchard analysis in the cerebellum showed that the K d value for binding to A3 receptors was 1.39 ± 0.04 nM with a B max of 14.8 ±2.1 protein. 3‐IB‐MECA at 0.1 i.p. was a locomotor depressant with > 50% reduction in activity. Although selective A1 or A2a antagonists reversed locomotor depression elicited by selective A1 or A2a agonists, respectively, the behavioral depressant effects of 3‐IB‐MECA were unaffected. 3‐IB‐MECA also caused scratching in mice, which was prevented by coadministration of the histamine antagonist cyproheptadine. The demonstration of a marked behavioral effect of A3 receptor activation suggests that the A3 receptor represents a potential new therapeutic target.