Pharmacological characterization of AMP 579, a novel adenosine A(1)/A(2) receptor agonist and cardioprotective

AMP 579 1S-[1 alpha,2 beta,3 beta,4 alpha(S*)]-4-[7-[[1-[(3-chloro-2-thieny l)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 s ystems: 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. Agonis m at A(2A) receptors was reflected in vasorelaxation of porcine coronary ar terial rings (IC50 = 0.3 mu M); in comparison, agonism at A(2B) receptors w as similar to 100-fold weaker, as reflected in relaxation of guinea pig aor ta (IC50 = 28 mu M). When given iv to conscious Sprague-Dawley (SD) rats, A MP 579 dose-dependentlly lowered free fatty acids (FFA), heart rate (HR), a nd mean arterial pressure (MAP), but was 25-fold more potent at reducing FF A 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 1 0 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 an d throughout the first hour of reperfusion. These cardioprotective doses of AMP 579 caused no significant change in blood pressure or coronary blood f low. In summary, AMP 579 is a novel adenosine A(1)/A(2A) receptor agonist w hich 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 poten tial for the therapy of acute myocardial infarction. Drug Dev. Res. 45:30-4 3, 1998. (C) 1998 Wiley-Liss, Inc.