A novel pharmacological approach to treating cardiac ischemia - Binary conjugates of A(1) and A(3) adenosine receptor agonists

Adenosine released during cardiac ischemia exerts a potent, protective effe ct in the heart via activation of A(1) or A(3) receptors. However, the inte raction between the two cardioprotective adenosine receptors and the questi on of which receptor is the more important anti-ischemic receptor remain la rgely unexplored. The objective of this study was to test the hypothesis th at activation of both receptors exerted a cardioprotective effect that was significantly greater than activation of either receptor individually. This was accomplished by using a novel design in which new binary conjugates of adenosine A(1) and A(3) receptor agonists were synthesized and tested in a novel cardiac myocyte model of adenosine-elicited cardioprotection. Binary drugs having mixed selectivity for both A(1) and A(3) receptors were creat ed through the covalent linking of functionalized congeners of adenosine ag onists, each being selective for either the A(1) or A(3) receptor subtype. MRS 1740 and MRS 1741, thiourea-linked, regioisomers of a binary conjugate, were highly potent and selective in radioligand binding assays for A(1) an d A(3) receptors (K-i values of 0.7-3.5 nM) versus A(2A) receptors. The myo cyte models utilized cultured chick embryo cells, either ventricular cells expressing native adenosine A(1) and A(3) receptors, or engineered atrial c ells, in which either human A(3) receptors alone or both human A(1) and A(3 ) receptors were expressed. The binary agonist MRS 1741 coactivated A(1) an d A(3) receptors simultaneously, with full cardioprotection (EC50 similar t o 0.1 nM) dependent on expression of both receptors, Thus, co-activation of both adenosine A(1) and A(3) receptors by the binary A(1)/A(3) agonists re presents a novel general cardioprotective approach for the treatment of myo cardial ischemia.