Inhibitors of membranous adenylyl cyclases with affinity for adenosine receptors.

Membrane-bound adenylyl cyclases constitute an interesting therapeutic target for various diseases that affect a large number of patients including asthma or congestive heart failure. Many inhibitors of adenylyl cyclases are competitive inhibitors at the ATP binding site and may, therefore, also interact with one or several of numerous ATP-binding proteins other than adenylyl cyclases. Several such inhibitors also show structural similarity to adenosine receptor ligands, providing a risk for side effects mediated by an unwanted interaction with these receptors. We have investigated a potential specific binding of four representative adenylyl cyclase inhibitors and found binding with pharmacologically relevant affinity to A1 and A2A receptors for NKY80 (2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone) and SQ22,536 (9-(tetrahydro-2-furanyl)-9H-purin-6-amine). These results underscore the importance to consider potential side effects mediated via adenosine receptors in the development of potent and specific inhibitors of adenylyl cyclases.