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

Merkel, Linda; Rojas, Camilo; Jarvis, Michael F.; Cox, Bryan F.; Fink, Cynthia A.; Smits, Glenn J.; Spada, Alfred P.; Perrone, Mark H.; Clark, Kenneth L.

doi:10.1002/(sici)1098-2299(199809)45:1<30::aid-ddr5>3.0.co;2-5

Cited by 12 publications

(13 citation statements)

References 45 publications

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“…For the majority of the functional assays, CPA was used as a standard reference A 1 agonist and the results are shown for comparison. The role of particular adenosine receptor subtypes in the functional responses to AMP 579 described in Table 2 was confirmed using subtype-selective antagonists (29).…”

Section: Functional Pharmacology In Vitromentioning

confidence: 82%

“…The methodology used to characterize the functional agonist effects in vitro of AMP 579 has previously been reported (19,29). For the majority of the functional assays, CPA was used as a standard reference A 1 agonist and the results are shown for comparison.…”

Section: Functional Pharmacology In Vitromentioning

confidence: 99%

“…In this regard, AMP 579 is currently undergoing pivotal phase II studies in patients suffering acute MI.The receptor binding affinities for adenosine receptor subtypes were determined by radioreceptor binding assays. Frozen rat epididymal fat pads and striatal brain tissue were used to characterize A 1 and A 2A receptors, respectively, using previously described methodology (19,29). For binding studies on A 2A and A 2B receptors, the human receptor was stably transfected into HEK-293 cells.Thus, in radioligand binding studies (Table 1), AMP 579 shows high affinity for both the adenosine A 1 and A 2A receptor subtypes with about a 10-fold selectivity for the A 1 receptor.…”

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confidence: 99%

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AMP 579, a Novel Adenosine Agonist for the Treatment of Acute Myocardial Infarction

Clark¹,

Merkel²,

Zannikos³

et al. 2000

Cardiovascular Drug Reviews

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The discovery that the endogenous autocoid adenosine plays a role in the ability of the myocardium to protect itself against ischemia has prompted a significant effort to identify stable cardioprotective adenosine agonists. This review summarizes current data regarding AMP 579, a novel adenosine receptor agonist with high affinity for the A 1 (K i = 2 nM) and A 2A (K i = 56 nM) receptor subtypes. In models of acute myocardial infarction (MI) in rats, pigs, and dogs, AMP 579 is a highly effective cardioprotective agent, when given prior to ischemia reducing infarct size by 63, 98, and 53%, respectively, and significantly reducing the incidence of ventricular fibrillation. Moreover, in rodent and porcine models of acute MI AMP 579 is still able to reduce infarct size by greater than 50% when administered just prior to reperfusion. This cardioprotective profile suggests that intravenous AMP 579 should prove therapeutically valuable when given as an adjunct to revascularization in patients suffering MI or undergoing coronary artery bypass grafting. Importantly, preclinical toxicology studies reveal no cause for concern regarding the potential therapeutic applications of AMP 579, which will entail only an acute intravenous administration. In addition, initial clinical experience with AMP 579 has been positive with an acceptable tolerability and a favorable pharmacokinetic profile, indicating that plasma levels of the drug can be rapidly and predictably controlled. Finally, the positive data from the Acute Myocardial Study of Adenosine (AMISTAD) trial, a small phase II study, indicate adenosine is able to reduce infarct size when given as an adjunct to thrombolysis in patients with anterior MI, raising confidence that the cardioprotective effects of adenosine agonists (e.g., AMP 579) seen in preclinical studies should translate into the clinic. In this regard, AMP 579 is currently undergoing pivotal phase II studies in patients suffering acute MI.

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Section: Functional Pharmacology In Vitromentioning

confidence: 82%

Section: Functional Pharmacology In Vitromentioning

confidence: 99%

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confidence: 99%

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AMP 579, a Novel Adenosine Agonist for the Treatment of Acute Myocardial Infarction

Clark¹,

Merkel²,

Zannikos³

et al. 2000

Cardiovascular Drug Reviews

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“…In common with other research groups, we observed a profound effect of exogenous agonists in the context of a model in which the levels of extracellular endogenous adenosine are elevated. 20,22,25,26 We titrated the time of ischemia against necrotic cell death and chose a time of ischemia (12 hours) that resulted in significant (48.42 6 8.11% of total cells) but not catastrophic cell death, so as to be able to observe both protection and worsening of ischemic cell death. In the presence of ADA, we observed an increased percentage of necrotic cells compared with the SI-alone treatment group (67.28 6 11.42% with reference to the SI group staining positively for PI), suggesting that increased (extracellular) endogenous adenosine after ischemic damage in the cells was responsible for protection from necrotic cell death.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotection Induced by Adenosine A1 Receptor Agonists in a Cardiac Cell Ischemia Model Involves Cooperative Activation of Adenosine A2A and A2B Receptors by Endogenous Adenosine

Urmaliya

Church

Coupar

et al. 2009

Journal of Cardiovascular Pharmacology

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Extracellular adenosine concentrations increase within the heart during ischemia, and any exogenous adenosine receptor agonists therefore work in the context of significant local agonist concentrations. We evaluated the interactions between A1, A2A, A2B, and A3 receptors in the presence and absence of adenosine deaminase (ADA, which is used to remove endogenous adenosine) in a cardiac cell ischemia model. Simulated ischemia (SI) was induced by incubating H9c2(2-1) cells in SI medium for 12 hours in 100% N2 gas before assessment of necrosis using propidium iodide (5 microM) or apoptosis using AnnexinV-PE flow cytometry. N6-Cyclopentyladenosine (CPA; 10(-7)M) and N6-(3-iodobenzyl) adenosine-5'-N-methyluronamide (IB-MECA; 10(-7)M) reduced the proportion of nonviable cells to 30.87 +/- 2.49% and 35.18 +/- 10.30%, respectively (% of SI group). In the presence of ADA, the protective effect of CPA was reduced (62.82 +/- 3.52% nonviable), whereas the efficacy of IB-MECA was unchanged (35.81 +/- 3.84% nonviable; P < 0.05, n = 3-5, SI vs. SI + ADA). The protective effects of CPA and IB-MECA were abrogated in the presence of their respective antagonists DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and MRS1191 [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate], whereas A2A and A2B agonists had no significant effect. CPA-mediated protection was abrogated in the presence of both A2A (ZM241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-lamino]ethyl)phenol; 50 nM) and A2B (MRS1754, 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(n-propyl)xanthine; 200 nM) antagonists (n = 3-5, P < 0.05). In the absence of endogenous adenosine, significant protection was observed with CPA in presence of CGS21680 (4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid) or LUF5834 [2-amino-4-(4-hydroxyphenyl)-6-(1H-imidazol-2-ylmethylsulfanyl)pyridine-3,5-dicarbonitrile] (P < 0.05 vs. SI + ADA + CPA). Apoptosis (14.35 +/- 0.15% of cells in SI + ADA group; P < 0.05 vs. control) was not significantly reduced by CPA or IB-MECA. In conclusion, endogenous adenosine makes a significant contribution to A1 agonist-mediated prevention of necrosis in this SI model by cooperative interactions with both A2A and A2B receptors but does not play a role in A3 agonist-mediated protection.

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“…This was a double-blind, multicenter, placebo-controlled trial of 311 patients undergoing primary percutaneous transluminal coronary angioplasty (PTCA) after acute ST-segment elevation MI (Kopecky et al 2003). Patients were randomly assigned to placebo or to one of three different doses of AMP579 (15, 30 or 60 μg kg −1 ) continuously infused over 6 h. This AR agonist, which has a high affinity for both A 1 and A 2A ARs, has been shown to reduce experimental myocardial ischemia-reperfusion in multiple species when administered both prior to ischemia or during reperfusion (Merkel et al 1998; McVey et al 1999; Meng et al 2000; Xu et al 2001; Kis et al 2003; Kristo et al 2004). The primary end-point was final myocardial infarct size measured by technetium Tc-99m sestamibi scanning at 120–216 h after PTCA.…”

Section: Reperfusion Injury and Ars In Human Myocardiummentioning

confidence: 99%

Adenosine Receptors and Reperfusion Injury of the Heart

Headrick

Lasley

2009

Adenosine Receptors in Health and Disease

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Adenosine, a catabolite of ATP, exerts numerous effects in the heart, including modulation of the cardiac response to stress, such as that which occurs during myocardial ischemia and reperfusion. Over the past 20 years, substantial evidence has accumulated that adenosine, administered either prior to ischemia or during reperfusion, reduces both reversible and irreversible myocardial injury. The latter effect results in a reduction of both necrosis or myocardial infarction (MI) and apoptosis. These effects appear to be mediated via the activation of one or more G-protein-coupled receptors (GPCRs), referred to as A 1 , A 2A , A 2B and A 3 adenosine receptor (AR) subtypes. Experimental studies in different species and models suggest that activation of the A 1 or A 3 ARs prior to ischemia is cardioprotective. Further experimental studies reveal that the administration of A 2A AR agonists during reperfusion can also reduce MI, and recent reports suggest that A 2B ARs may also play an important role in modulating myocardial reperfusion injury. Despite convincing experimental evidence for AR-mediated cardioprotection, there have been only a limited number of clinical trials examining the beneficial effects of adenosine or adenosine-based therapeutics in humans, and the results of these studies have been equivocal. This review summarizes our current knowledge of AR-mediated cardioprotection, and the roles of the four known ARs in experimental models of ischemia-reperfusion. The chapter concludes with an examination of the clinical trials to date assessing the safety and efficacy of adenosine as a cardioprotective agent during coronary thrombolysis in humans.

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

Cited by 12 publications

References 45 publications

AMP 579, a Novel Adenosine Agonist for the Treatment of Acute Myocardial Infarction

AMP 579, a Novel Adenosine Agonist for the Treatment of Acute Myocardial Infarction

Cardioprotection Induced by Adenosine A1 Receptor Agonists in a Cardiac Cell Ischemia Model Involves Cooperative Activation of Adenosine A2A and A2B Receptors by Endogenous Adenosine

Adenosine Receptors and Reperfusion Injury of the Heart

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