Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

AMP 579 1S-[1 alpha,2 beta,3 beta,4 alpha(S*)]-4-[7-[[1-[(3-chloro-2-thienyl)methyl]propylamino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxy cyclopentanecarboxamide) is a novel cardioprotective adenosine agonist with the following order of affinity at adenosine receptors: A(1) > A(2A) > A(3). Agonism at A(1) receptors was demonstrated in vitro in three different systems: 1) inhibition of lipolysis in rat and human isolated adipocytes, 2) restoration of insulin-dependent glucose transport in rat adipocytes, and 3) reduction of heart rate in spontaneously beating rat right atria. Agonism at A(2A) receptors was reflected in vasorelaxation of porcine coronary arterial rings (IC50 = 0.3 mu M); in comparison, agonism at A(2B) receptors was similar to 100-fold weaker, as reflected in relaxation of guinea pig aorta (IC50 = 28 mu M). When given iv to conscious Sprague-Dawley (SD) rats, AMP 579 dose-dependentlly lowered free fatty acids (FFA), heart rate (HR), and mean arterial pressure (MAP), but was 25-fold more potent at reducing FFA than at decreasing HR and MAP. In anesthetized rats undergoing myocardial ischemia-reperfusion injury, AMP 579 (3 mu g/kg + 0.3 mu g/kg/min iv and 10 mu g/kg + 1 mu g/kg/min iv) was able to reduce infarct size by 55% and 63%, respectively, compared to control animals, when given 10 min prior to and throughout the first hour of reperfusion. These cardioprotective doses of AMP 579 caused no significant change in blood pressure or coronary blood flow. In summary, AMP 579 is a novel adenosine A(1)/A(2A) receptor agonist which causes long-lasting reductions in FFA in vivo and has cardioprotective effects in a rat model of myocardial ischemia-reperfusion injury at doses which have minimal hemodynamic effects. Thus, AMP 579 has significant potential for the therapy of acute myocardial infarction. Drug Dev. Res. 45:30-43, 1998. (C) 1998 Wiley-Liss, Inc.