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J. Biol. Chem., Vol. 275, Issue 39, 30272-30279, September 29, 2000

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A Novel Pharmacological Approach to Treating Cardiac Ischemia
BINARY CONJUGATES OF A₁ AND A₃ ADENOSINE RECEPTOR AGONISTS^*

Kenneth A. Jacobson^§, Rongyuan Xie, Laura Young^¶, Louis Chang, and Bruce T. Liang^¶

From the  Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and the ^¶ Department of Medicine, Cardiovascular Division and Department of Pharmacology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart via activation of A₁ or A₃ receptors. However, the interaction between the two cardioprotective adenosine receptors and the question of which receptor is the more important anti-ischemic receptor remain largely unexplored. The objective of this study was to test the hypothesis that 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 A₁ and A₃ receptor agonists were synthesized and tested in a novel cardiac myocyte model of adenosine-elicited cardioprotection. Binary drugs having mixed selectivity for both A₁ and A₃ receptors were created through the covalent linking of functionalized congeners of adenosine agonists, each being selective for either the A₁ or A₃ receptor subtype. MRS 1740 and MRS 1741, thiourea-linked, regioisomers of a binary conjugate, were highly potent and selective in radioligand binding assays for A₁ and A₃ receptors (K_i values of 0.7-3.5 nM) versus A_2A receptors. The myocyte models utilized cultured chick embryo cells, either ventricular cells expressing native adenosine A₁ and A₃ receptors, or engineered atrial cells, in which either human A₃ receptors alone or both human A₁ and A₃ receptors were expressed. The binary agonist MRS 1741 coactivated A₁ and A₃ receptors simultaneously, with full cardioprotection (EC₅₀ ~0.1 nM) dependent on expression of both receptors. Thus, co-activation of both adenosine A₁ and A₃ receptors by the binary A₁/A₃ agonists represents a novel general cardioprotective approach for the treatment of myocardial ischemia.

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