Ap. Ijzerman et al., PARTIAL AGONISM OF THEOPHYLLINE-7-RIBOSIDE ON ADENOSINE RECEPTORS, Naunyn-Schmiedeberg's archives of pharmacology, 350(6), 1994, pp. 638-645
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.