title: Partial agonism of theophylline-7-riboside on adenosine receptors.
abstract: Theophylline-7-riboside was evaluated as a partial agonist for rat adenosine receptors. Radioligand binding experiments were performed on both A1 and A2a adenosine receptors, using several methodologies to discriminate between agonists and antagonists. Mainly from thermodynamic data it was concluded that on A1 receptors theophylline-7-riboside had characteristics intermediate between full agonists, such as N6-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-riboside behaved as a partial agonist for A1 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 A1 or A2a 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 EC50 value of theophylline-7-riboside for lowering the mean arterial pressure was 47 +/- 12 micrograms/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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Center for Bio-Pharmaceutical Sciences, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: E M
authors.initials: EM
authors.lastname: van der Wenden
authors.forename: J K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: R A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: P A
authors.initials: PA
authors.lastname: Borea
authors.forename: K
authors.initials: K
authors.lastname: Varani
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D006160:Guanosine Triphosphate; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D013696:Temperature; D013806:Theophylline / Q000819:agonists* / Q000494:pharmacology; D019820:Xanthine; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D019820:Xanthine; D005576:Colforsin; D006160:Guanosine Triphosphate; D013806:Theophylline