ATL-193

Background — Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A 2A Ado receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5′- N -ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging. Methods and Results — In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A 2A over the A 1 and A 3 receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of 99m Tc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A 2A antagonist ZM241385 (3 μg · kg −1 · min −1 ). Conclusions — ATL-193 and ATL-146e are highly potent and selective Ado A 2A receptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.

Novel 2‐propynylcyclohexyl‐5′‐N‐ehtylcarboxamidoadenosines, trans‐substituted in the 4‐position of the cyclohexyl ring, were evaluated in binding assays to the four subtypes of adenosine receptors (ARs). Two esters, 4‐{3‐[6‐amino‐9‐(5‐ethylcarbamoyl‐3,4‐dihydroxy‐tetrahydro‐furan‐2‐yl)‐9H‐purin‐2‐yl]‐prop‐2‐ynyl}‐cyclohexanecarboxylic acid methyl ester (ATL146e) and acetic acid 4‐{3‐[6‐amino‐9‐(5‐ethylcarbamoyl‐3, 4‐dihydroxy‐tetrahydro‐furan ‐2‐yl)‐9H‐purin‐2‐yl] ‐prop‐2‐ynyl}‐cyclohexylmethyl ester (ATL193) were >50×more potent than 2‐[4‐(2‐carboxyethyl)phenethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS21680) for human A2A AR binding. Human A2A AR affinity for substituted cyclohexyl‐propynyladenosine analogues was inversely correlated with the polarity of the cyclohexyl side chain. There was a comparable order of potency for A2A AR agonist stimulation of human neutrophil [cyclic AMP]i, and inhibition of the neutrophil oxidative burst. ATL146e and CGS21680 were ∼equipotent agonists of human A3 ARs.We measured the effects of selective AR antagonists on agonist stimulated neutrophil [cyclic AMP]i and the effect of PKA inhibition on A2A AR agonist activity. ATL193‐stimulated neutrophil [cyclic AMP]i was blocked by antagonists with the potency order: ZM241385 (A2A‐selective)>MRS1220 (A3‐selective)>>N‐(4‐Cyano‐phenyl)‐2‐[4‐(2,6‐dioxo‐1,3‐dipropyl‐2,3,4,5,6,7‐hexahydro‐1H‐purin‐8‐yl)‐phenoxy]‐acetamide (MRS1754; A2B‐selective) ∼amp; 8‐(N‐methylisopropyl)amino‐N6‐(5′‐endohydroxy‐endonorbornyl)‐9‐methyladenine (WRC0571; A1‐selective). The type IV phosphodiesterase inhibitor, rolipram (100 nM) potentiated ATL193 inhibition of the oxidative burst, and inhibition by ATL193 was counteracted by the PKA inhibitor H‐89.The data indicate that activation of A2AARs inhibits neutrophil oxidative activity by activating [cyclic AMP]i/PKA.British Journal of Pharmacology (2001) 132, 1017–1026; doi:10.1038/sj.bjp.0703893