New potent and selective human adenosine A 3 receptor antagonists

Abstract

Adenosine regulates many physiological functions via specific cell membrane receptors. To date, four adenosine receptor subtypes have been cloned, A1, A2A, A2B and A3, each of which exhibits a unique tissue distribution, ligand affinity and signal transduction mechanism 1. Fredholm B.B. et al. Nomenclature and classification of purinoceptors. Pharmacol. Rev. 1994; 46: 143-156 PubMed Google Scholar . A1 and A2A receptors are activated by nanomolar concentrations of adenosine whereas A2B and A3 subtypes become activated only when adenosine levels increase into the micromolar range during periods of inflammation, hypoxia or ischemia 2. Jacobson K.A. et al. A3 adenosine receptors: design of selective ligands and therapeutic prospects. Drugs Future. 1995; 20: 689-699 Google Scholar , 3. Olah M.E. Stiles G.L. Adenosine receptor subtypes: characterization and therapeutic regulation. Annu. Rev. Pharmacol. Toxicol. 1995; 35: 581-606 Crossref PubMed Google Scholar . Thus, the pathophysiological role of the A3 receptor might be very different from that of A1 and A2A subtypes, in that A3 receptors could act as endogenous regulators under conditions of more severe challenge 4. Jacobson K.A. Adenosine A3 receptors: novel ligands and paradoxical effects. Trends Pharmacol. Sci. 1998; 19: 184-191 Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar . To fully evaluate the pathophysiological role of these receptors, subtype-selective agonists and antagonists with high affinity are required.