Theophylline-7-riboside

Figure 3. Van t Hoff plots showing the effect of temperature on the equilibrium association constants, K, of both xanthines ( theophylline 1,3-dipropylxanthine x 1,3-dibutylxanthine) and xanthine-7-ribosides ( theophylline-7-riboside O 1,3-dipropyl-xanthine-7-riboside a 1,3-dibutylxanthine-7-riboside). All plots were essentially linear (r > 0.95). Reproduced with permission of principal author and publisher of ref. [34].

Based on these findings, theophylline-7-riboside was selected for in vivo studies. In Fig. 4 the effects of an intravenous infusion of theophylline-7-riboside (80 mg/kg rat) in 5 minutes are represented. In pilot studies it was found that this dosage yielded maximal effects. Infusion of the vehicle alone, despite the high concentration of DMSO present, did not change the baseline heart rate and blood pressure significantly. The decrease in MAP (Fig. 4a) observed with theophylline-7-riboside, although substantial from 100 mm Hg to... 

Figure 4. Effect of a 5 min infusion of theophylline-7-riboside (80 mg/kg) in unrestrained, conscious and normotensive rats on a) mean arterial pressure and b) heart rate. Results are the means ( SE) of data obtained in 3 rats. Rats were observed during 5.5 h after administration, with no changes in parameters after 1 h. Reproduced with permission of principal author and publisher of ref. [34].

The rise in heart rate (Fig. 4b) observed within the first minutes of infusion is probably best described as a reflex tachycardia. The same phenomenon has also been observed with the Aj -selective full agonist CGS 21680. The latter compound, however, reached peak values (data not shown) as high as 550 beats per minute (bpm), contrasting to the mean highest value for theophylline-7-riboside of 425 bpm. CPA in the same experimental setup caused a decrease in heart rate to as low as 150 bpm. Thus, theophylline-7-riboside behaved as a partial agonist on parameters that are strictly A, receptor mediated (heart rate) or both A and Aj (mean arterial pressure). In conclusion, theophylline-7-riboside, developed from the antagonist theophylline, may be a useful tool as a partial agonist for adenosine receptors. Its low affinity is a potential drawback, which warrants the development of other compounds for which theophylline-7-riboside may be a lead. 

Because of the great interest in the naturally occurring nucleosides, studies of the synthesis of D-ribosides of purines and pyrimidines have been numerous. The first attempt in this direction was made by Levene and Sobotka146 who condensed the silver salt of theophylline with tri-acetyl- 8-D-ribopyranosyl bromide to obtain what was probably triacetyl-7- 8-D-ribopyranosyl theophylline (LXXVI). Subsequently Hilbert and Rist94 condensed 2,4-diethoxypyrimidine (LXXVII) with triacetyl-0-D-ribopyranosyl bromide (LXXVIII) to form ethyl bromide and 1-triacetyl-D-ribopyranosyl-4-ethoxyuracil (LXXX), which, on deacetylation with hydrogen chloride, gave 1-D-ribopyranosyluracil (LXXIX), an isomer of... 

Subsequently, we synthesized the 7-ribosides of theophylline, 1,3-dipropylxanthine and 1,3-dibutylxanthine [46]. The Kj values at 25 °C of the three xanthines, the corresponding xanthine-7-ribosides and the reference full agonist R-PIA were obtained in radioligand binding studies with the tritiated agonist N -cyclohexyladenosine (CHA) on rat brain membranes. The results are summarized in Table 1. 

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