Glover D K, Ruiz M, Takehana K, Petruzella F D, Riou L M, Rieger J M, Macdonald T L, Watson D D, Linden J, Beller G A
Experimental Cardiology Laboratory, Cardiovascular Division, Department of Internal Medicine, University of Virginia Health System, Charlottesville, USA.
Circulation. 2001 Sep 4;104(10):1181-7. doi: 10.1161/hc3601.093983.
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.
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 microgram. kg(-1). min(-1)).
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.
腺苷（Ado）和双嘧达莫是用于心肌灌注成像的运动负荷替代药物。尽管通常安全，但副作用频繁发生，会导致患者不适，有时会导致研究提前终止或需要使用氨茶碱。最近，合成了一类新的A(2A)腺苷受体激动剂。ATL193和ATL146e是腺苷的2-丙炔基环己基-5'-N-乙基羧酰胺衍生物。研究目的是评估这些新化合物对重组犬腺苷受体的效力和选择性，并评估它们在犬体内的血流动力学特性，以评估其作为心肌灌注成像血管扩张剂的实用性。
在重组犬腺苷受体测定中，ATL-193和ATL-146e对A(2A)受体的选择性高于A(1)和A(3)受体，且比MRE-0470和CGS-21680更有效。在16只麻醉犬中，通过输注（ATL-193；n = 7只正常犬）或推注（ATL-146e；n = 9只左前降支冠状动脉严重狭窄犬）给予激动剂，并将血流动力学反应与腺苷的反应进行比较。两种激动剂均产生剂量依赖性冠状动脉血流（CF）升高，且未引发腺苷所致的低血压。推注ATL-146e后，CF升高持续数分钟，为注射和心肌摄取（99m）Tc-司他米比提供了充足时间，且CF在20分钟内恢复至基线。CF升高被选择性A(2A)拮抗剂ZM241385（3微克·kg(-1)·min(-1)）完全阻断。
ATL-193和ATL-146e是高效且选择性的腺苷A(2A)受体激动剂，具有作为心肌灌注成像血管扩张剂的极佳潜力。ATL-146e的一个重要优点是能够通过推注给药。
