PARTIAL AGONISM OF THEOPHYLLINE-7-RIBOSIDE ON ADENOSINE RECEPTORS

Theophylline-7-riboside was evaluated as a partial agonist for rat adenosine receptors. Radioligand binding experiments were performed on both A(1) and A(2a) adenosine receptors, using several methodologies to discriminate between agonists and antagonists. Mainly from thermodynamic data it was concluded that on A(1) receptors theophylline-7-riboside had characteristics intermediate between full agonists, such as N-6-cyclopentyladenosine, and full antagonists, such as the xanthines. The partial agonistic behaviour of theophylline-7-riboside was further explored in second messenger studies in intact cells. In FRTL-5 rat thyroid cells theophylline-7-ribo- side behaved as a partial agonist for A(1) receptors, slightly inhibiting forskolin-stimulated cyclic AMP levels. The implications of these biochemical findings were further analysed in in vivo pharmacology. The infusion of theophylline-7-riboside in conscious, normotensive rats led to marked changes in cardiovascular parameters, although less outspoken than observed with full agonists for either A(1) or A(2a) receptors. The concomitant determination of the blood concentrations of theophylline-7-riboside and its metabolite theophylline allowed the estimation of in vivo pharmacokinetic and pharmacodynamic parameters. Thus, the EC(50) value of theophylline-7-riboside for lowering the mean arterial pressure was 47 +/- 12 mu g/ml blood. The short duration of action of theophylline-7-riboside makes it improbable that its metabolite theophylline interferes with its effects. In conclusion, theophylline-7-riboside is one of the first partial agonists for adenosine receptors. It may serve as a tool in further investigations of adenosine receptor partial agonism.