Drugs modulating adenosine receptors as potential therapeutic agents for cardiovascular diseases

Adenosine has a wide range of physiological activities arising from its int eraction with the P-1 purinoceptor, which has been further subclassified in to four types - A(1), A(2A), A(2B) and A(3). Apart from adenosine itself an d long-established antagonists such as theophylline and caffeine there are no new adenosine receptor agonist or antagonist drug molecules currently in clinical use. In view of the widespread actions of adenosine in the cardio vascular system and the possible role of adenosine in the pathogenesis of m any diseases affecting the cardiovascular system, new agents that modulate adenosine's actions have considerable therapeutic potential. The main disea ses under consideration in this review of patents from 1997 - 2000 are hype rtension, myocardial ischaemia (infarction), cerebral ischaemia (stroke), s upraventricular tachycardia, renal failure, heart failure and peripheral is chaemia (intermittent claudication). Novel agonists and antagonists at each of the four receptor subtypes have been disclosed, except A(2B) agonists, where a gap still remains. Agents that raise endogenous adenosine levels, n amely inhibitors of adenosine transport, adenosine deaminase and adenosine kinase, are also disclosed. Claims are made for the potential use of all of the agents in the treatment of cerebral and myocardial ischaemia. The like ly mechanisms for this protective action are not always clear and the final therapeutic outcome must remain uncertain until the underlying mechanisms are resolved. Applications in the treatment of renal dysfunction and as diu retics are claimed for novel adenosine A(1) receptor antagonists which appe ar to be more realistic. There is growing interest in the role of adenosine in inflammatory disorders as they relate to cerebrovascular and myocardial ischaemia and actions of adenosine receptor agonists and antagonists on ne utrophil and mast cell function appear to show particular promise. The only established use of adenosine in the treatment of supraventricular arrythmi as has received some additional support with the disclosure of several nove l A(1) receptor agonists. A(1)-selective agonists with potential for hyperl ipidaemias, arrhythmias following myocardial infarction, heart failure and hypertension, are also disclosed.