A₁-Adenosine receptor antagonists

Abstract

Potent and selective A₁-adenosine receptor (AR) antagonists (derivatives of xanthine or other heterocyclic structures) have been developed during the past ten years. Recently, the problem of low water solubility found with these groups of compounds has been addressed with the introduction of hydrophilic groups in positions tolerated by the receptor. Cloning of the A₁-AR of several species, including humans, has allowed mutagenesis studies to identify the binding site for agonists and antagonists. Computer modelling of the pharmacophore has been useful for developing more potent and selective ligands. Modelling of the receptor protein was attempted, but remains speculative. The first generation of A₁-selective AR antagonists is under clinical development for different indications, including dementias, such as Alzheimer’s disease, hypertension and renal failure. New potential indications are being discovered and investigated, particularly in heart (treatment of cardiac arrhythmias, oedemas, as positive inotropes and as cardiac protectants), kidney (treatment of oedemas, nephritis, nephrosis syndrome), lung (asthma, oedema, lung protective) and central nervous system (CNS) (depression, stress, coma) diseases. A₁-selectivity is important for specific actions and for reducing undesired side-effects, e.g., increase in locomotor activity.