Drugs modulating adenosine receptors as potential therapeutic agents for cardiovascular diseases

Adenosine has a wide range of physiological activities arising from its interaction with the P-1 purinoceptor, which has been further subclassified into four types - A(1), A(2A), A(2B) and A(3). Apart from adenosine itself and 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 cardiovascular system and the possible role of adenosine in the pathogenesis of many diseases affecting the cardiovascular system, new agents that modulate adenosine's actions have considerable therapeutic potential. The main diseases under consideration in this review of patents from 1997 - 2000 are hypertension, myocardial ischaemia (infarction), cerebral ischaemia (stroke), supraventricular tachycardia, renal failure, heart failure and peripheral ischaemia (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, namely 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 likely 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 diuretics are claimed for novel adenosine A(1) receptor antagonists which appear 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 neutrophil and mast cell function appear to show particular promise. The only established use of adenosine in the treatment of supraventricular arrythmias has received some additional support with the disclosure of several novel A(1) receptor agonists. A(1)-selective agonists with potential for hyperlipidaemias, arrhythmias following myocardial infarction, heart failure and hypertension, are also disclosed.