PARTIAL AGONISM OF THEOPHYLLINE-7-RIBOSIDE ON ADENOSINE RECEPTORS

Theophylline-7-riboside was evaluated as a partial agonist for rat ade nosine receptors. Radioligand binding experiments were performed on bo th A(1) and A(2a) adenosine receptors, using several methodologies to discriminate between agonists and antagonists. Mainly from thermodynam ic data it was concluded that on A(1) receptors theophylline-7-ribosid e 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 ex plored in second messenger studies in intact cells. In FRTL-5 rat thyr oid cells theophylline-7-ribo- side behaved as a partial agonist for A (1) receptors, slightly inhibiting forskolin-stimulated cyclic AMP lev els. The implications of these biochemical findings were further analy sed in in vivo pharmacology. The infusion of theophylline-7-riboside i n 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 t he blood concentrations of theophylline-7-riboside and its metabolite theophylline allowed the estimation of in vivo pharmacokinetic and pha rmacodynamic parameters. Thus, the EC(50) value of theophylline-7-ribo side for lowering the mean arterial pressure was 47 +/- 12 mu g/ml blo od. The short duration of action of theophylline-7-riboside makes it i mprobable that its metabolite theophylline interferes with its effects . In conclusion, theophylline-7-riboside is one of the first partial a gonists for adenosine receptors. It may serve as a tool in further inv estigations of adenosine receptor partial agonism.