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1 Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, CT, USA
* To whom correspondence should be addressed. E-mail: w_ross_tracey{at}groton.pfizer.com.
We recently reported the identification of a novel human adenosine A3 receptor-selective agonist, CP-608,039 ((2S, 3S, 4R, 5R)-3-amino-5-{6-[5-chloro-2-(3-methyl-isoxazol-5-ylmethoxy)-benzylamino]-purin-9-yl}-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide), with 1260-fold selectivity for the hA3 vs. hA1 receptor (DeNinno et al., J. Med. Chem. 46: 353-355, 2003). However, since the modest (20-fold) rabbit A3 receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, CP-532,903 ((2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichloro-benzylamino)-purin-9-yl]-4-hydroxy-tetrahydro-furan-2-carboxylic acid methyl amide) which both retained human A3 receptor selectivity (210-fold; hA3/hA1 Ki: 23/4,800 nM) and had improved rabbit A3 receptor selectivity (90-fold; rA3/rA1 Ki: 23/2,000 nM). Infarct size was measured in Langendorff hearts or in vivo following 30 min of regional ischemia and 120 min of reperfusion. Five min perfusion with CP-532,903 before ischemia-reperfusion elicited a concentration-dependent reduction in infarct size in isolated hearts (EC50: 0.97 nM; maximum reduction in infarct size: 77%, P < 0.05 vs. control). Furthermore, administration of CP-532,903 (150 nM) at reperfusion also significantly reduced infarct size by 64% (P < 0.05 vs. control), which was not different (P 
0.05) from the cardioprotection provided by the same concentration of drug given prior to ischemia. The selective rabbit A1 receptor antagonist, BWA1433, did not affect CP-532,903-dependent cardioprotection. In vivo, CP-532,903 (1 mg/kg) reduced infarct size by 50%, in the absence of significant hemodynamic effects (mean arterial pressure, heart rate, rate pressure product). CP-532,903 and CP-608,039 represent a novel class of human A3 receptor-selective agonists that may prove suitable for investigation of the clinical cardioprotective efficacy of A3 receptor activation.
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