Ligands for A2B adenosine receptor subtype

Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A(1), A(2A), A(2B), and A(3). The A(2B) subtype is a low affinity receptor, which couples to stimulation of adenylyl cyclase and also leads to a rise in intracellular calcium modulating important physiological processes. Adenosine exhibiting activity at this subtype is at concentrations greater than 10 microM. The A(2B) receptors show a ubiquitous distributions, the highest levels are present in cecum, colon and bladder, followed by blood vessels, mast cells and lung. Through A(2B) receptors, adenosine also regulates the growth of smooth muscle cell populations in blood vessels, cell growth, intestinal function, inhibition of Tumor Necrosis Factor (TNF-alpha), vascular tone, and inflammatory processes such as diarrhea and asthma. Potent and selective adenosine agonists are the result of modifications of the parent ligand adenosine by substitution, namely at N(6) or C(2) position of the purine heterocycle or at the 5' position of the ribose moiety. 5'-N-ethylcarboxamidoadenosina (NECA) is one of the most potent A(2B) adenosine receptor agonist. Classical antagonists for A(2B) adenosine receptors are xanthine analogues obtained from multiple substitutions of the parent heterocycle by C(8) substitution combined with N(1) and N(3) (and sometimes N(7)) substitutions.