8-Aminopurines: A Promising New Direction for Purine-Based Therapeutics.

Research in purinergic pharmacology has yielded major advances in cardiovascular therapeutics such as adenosine for terminating atrioventricular reentrant tachycardia, regadenoson for pharmacological ischemic stress testing, and selective P2Y receptor antagonists for prevention of stroke and myocardial infarction. Mechanistically, these FDA-approved purine-based therapeutics activate or antagonize receptors having endogenous ligands containing the purine nucleobase adenine. Recent discoveries suggest a novel direction for purine-based therapeutics. An investigation of the cardiorenal effects of 8-substituted guanosine and guanine derivatives revealed that 8-aminoguanosine and 8-aminoguanine acutely trigger diuresis, natriuresis, and glucosuria, with the effects of 8-aminoguanosine being mediated by its rapid conversion to 8-aminoguanine. Mechanistic studies showed that 8-aminoguanine induces diuresis/natriuresis/glucosuria in part by inhibiting purine nucleoside phosphorylase (PNPase). Inhibition of PNPase increases its substrates (inosine and guanosine) while decreasing its products (hypoxanthine and guanine), thus “rebalancing” the purine metabolome. Additional mechanistic studies revealed that inosine activates adenosine A receptors which increases renal medullary blood flow thus enhancing renal excretory function. 8-Aminoguanine also reduces potassium excretion by an incompletely understood mechanism independent of PNPase inhibition. Emerging evidence suggests the existence of a family of endogenous and pharmacologically active 8-aminopurines that may include not only 8-aminoguanosine and 8-aminoguanine, but also 8-aminoinosine, 8-aminohypoxanthine and 8-aminoxanthine. 8-Aminopurines have beneficial effects in animal models of systemic and pulmonary hypertension, the metabolic syndrome, chronic kidney disease, strokes, and sickle cell disease. Also, 8-aminopurines reverse age-associated lower urinary tract dysfunction and retinal degeneration. 8-Aminopurines hold promise for treating cardiovascular and renal diseases and may “turning back the clock” on age-associated disorders.