A1 and A3 adenosine receptor agonists:: an overview

Adenosine regulates several physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four distinct adenosine receptors have been identified and classified as A(1), A(2A), A(2B) and A(3). These adenosine receptors are members of the G-protein coupled receptor family, but while A(2A) and A(2B) receptors stimulate adenylyl cyclase with a consequent increase of cAMP levels, A(1) and A(3) receptor subtypes produce the opposite effect. Intense efforts made over the last 20 years have led to the synthesis of a variety of selective adenosine agonists. In general, all of the compounds thus far identified are related to the adenosine structure. The A(1) receptors are usually found on the working cells of tissues (e.g., neurones and cardiomyocytes) and mediate decreases in oxygen demand; for these reasons A(1) agonists could be useful for the treatment of, for example, renal failure, arrhythmias, diabetes Type II, myocardial ischaemia and neurodegenerative disorders. The A(3) receptor is not yet well known. This receptor subtype seems involved in inflammatory and neurodegenerative diseases, asthma and cardiac ischaemia but some paradoxical effects have been observed. On this basis, the recent developments on structure-activity relationships at A(1) and A(3) receptors and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature.