Tachycardia adenosine receptor agonists

PI (adenosine) receptors were explored as therapeutic targets before P2 receptors. Adenosine was identified early and is in current use to treat supraventricular tachycardia. A2a receptor antagonists are being investigated for the treatment of Parkinson s disease and patents have been lodged for the application of PI receptor subtype agonists and antagonists for myocardial ischaemia and reperfusion injury, cerebral ischaemia, stroke, intermittent claudication and renal insufficiency. 

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. 

Presently, only adenosine itself is approved for clinical use. It is used widely in the treatment of supraventricular tachycardia and in cardiac stress imaging to assess coronary artery disease [5]. Other agonists and antagonists and an allosteric modulator of the Ai receptor are in clinical trials for a variety of indications. 

Research on compounds that interact with adenosine A1 receptors has focused on agonists with structures based on adenosine itself as agents that will overcome responses due to inappropriate excitation such as tachycardia and some arrhythmias. Replacement of one of the hydrogen atoms on the exocyclic amine in adenosine by a tetrahydrofuryl group provides an effective A1 adenosine agonist. Preparation of this fragment as a single enantiomer starts with a modem version of the Curtius reaction. 

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