Adenosine receptors: pharmacology, structure-activity relationships, and therapeutic potential.

In the 10 years since Daly reviewed1 the potential of adenosine receptors as drug targets, considerable advances have been made in the area of purinergic receptor related research such that there is little doubt remaining that adenosine, as well as adenosine 5′-triphosphate (ATP) and related nucleotides, functions as both neurohumoral agents and autacoids regulating the process of cell to cell communication.2 The techniques of molecular pharmacology have been extensively used to delineate purinergic receptor function, resulting in the identification of several receptor subclasses that subserve discrete physiological functions (Table I). 2 And more recently, the two major classes of adenosine receptors, the A1 and A2, have been cloned,3,4 offering the potential to model the receptor–ligand interaction from the receptor side.5 Table I Purinoceptor Subtypes On the ligand front, structure–activity relationships (SAR) studies (Figure 1) for derivatives of adenosine (1), as agonists, and of theophylline (2), as antagonists, have revealed selective agents,6–8 and potent and selective A1- and A2-receptor agonists are now available. Newer antagonist ligands include a large number of 8-substituted xanthine derivatives, some of them over 10000-fold more potent than the parent compound 2, as well as numerous classes of non-xanthine heterocyclic compounds8 described in further detail below. Figure 1 The structures of adenosine (1) and theophylline (2), showing the effects of structural modifications at various sites on receptor binding. The exceptional progress in the preclinical area, both chemical and biological, has not however been paralleled in the clinic. Very few adenosine agonists and antagonists have entered clinical trials and none of these, to the authors’ knowledge, have been successful.7 The only approved compound known to produce its therapeutic actions via a direct interaction with adenosine receptors is adenosine itself, used for the treatment of supraventricular tachycardia (SVT),9 a use designated by the U.S. Food and Drug Administration in their coveted 1A category, indicating a drug for major unmet medical need. Additional potential uses for adenosine include cardiac imaging,10 in cardioplegic solutions11 to delay the onset of ischemic contractions, and as a cardioprotectant in postischemic reperfusion.12 While caffeine and theophylline represent prototypic, albeit weak, adenosine antagonists, second generation forms of these compounds with improved antagonist activity for use as cardiotonics, cognition enhancers or antiasthmatics have not been forthcoming despite considerable chemical effort.8 The reasons for the limited progress in adenosine therapeutics are several-fold and include the ubiquity of action of adenosine (and ATP) on a variety of diverse tissue systems, a paucity of receptor selective ligands that are orally bioavailable and soluble, lack of knowledge of disease states involving a purinergic etiology, and probably most importantly, a failure to target adenosine agents in terms of unmet therapeutic need.13 Thus, agonists have been routinely targeted toward hypertension, an area where these agents have probable CNS and renal side effects and compare unfavorably with the many excellent and efficacious antihypertensive agents currently available in the clinic.13 In the present perspective, advances in knowledge related to adenosine function at the molecular level will be reviewed together with information on the structure–activity relationships for a number of pharmacophore series interacting with adenosine receptors. Therapeutic areas where improved adenosine ligands may represent potentially important therapeutic agents will also be indicated.