Chemical and pharmacological profile of selective adenosine receptor agonists

There is evidence that the purine nucleoside adenosine specifically modulates neurotransmission through the interaction with four cell surface receptors recently classified as A1, A2a, A2b, and A3. These receptor subtypes have been cloned and characterized as belonging to the superfamily of receptors with seven transmembrane helices that couple to G proteins. Over the last decade a large number of adenosine analogs with high affinity and selectivity for A1 and A2a and, more recently, A3 receptors have been synthesized. However, the existence of at least four AR subtypes necessitates the generation of more discriminating compounds which may ultimately have therapeutic use. More in detail, selective A1 receptor agonist might be of therapeutical interest as antiarrhythmic and cardioprotective agents since: a) the cardiodepressant effects of adenosine appear to be important in the pathogenesis of arrhythmias in ischemic heart disease; b) adenosine exerts A1-mediated cardioprotective action in preconditioning, a phenomenon by which one or more brief periods of ischemia result in improved functional recovery after substained ischemia. Selective A2a receptor agonists have a potential for the treatment of cardiovascular disorders such as hypertension, ischemic heart disease, and atherosclerosis since it is known that stimulation of adenosine A2a receptors leads to vasodilation, inhibition of platelet aggregation, and neutrophil adhesion to vascular endothelium, and reduction in generation of oxygen free radicals by activated neutrophils. Selective A3 receptor antagonists have potential use in the treatment of asthmatic and other allergic conditions, and may afford cardioprotection from prolonged ischemia. In this paper our contribution both to the improvement of structure-activity relationships and to the development of A1 and A2a potent and selective agonist will be reported.