Activation of Adenosine A1 and A3 Receptors Protects Mitochondria during Hypoxia in Cardiomyocytes by Distinct Mechanisms

Shneyvays, Vladimir; Leshem, Dorit; Mamedova, L.K.; Shainberg, Asher

doi:10.1007/978-1-4615-0355-2_24

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…Compound 6 (MW 45 KD) is close in structure to multivalent conjugate 2 . For use as pharmacological probes of ARs, the A 3 AR-selective 2 and 6 are preferred over 1 that also binds to the A 1 AR, which has its own distinct cardiovascular effects [14,15,27,36]. Also, the 2-alkynyl group present in 2 and 6 was previously associated with improved consistency of A 3 AR affinity between species [26].…”

Section: Discussionmentioning

confidence: 99%

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Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Chanyshev

Shainberg

Isak

et al. 2012

Pharmacological Research

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Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A3 adenosine receptor (AR) agonists, chain-functionalized at the C2 or N6 position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A1 and A3ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A3AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A3AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A3AR on the cardiomyocyte surface.

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Section: Discussionmentioning

confidence: 99%

“…Cardiomyocyte cultures [27,28] were washed in serum- and glucose-free medium before being incubated in the presence of AR ligands, under hypoxic conditions. Exposure to argon (100%) in a hypoxic chamber in glucose-free media for 90 min was used to simulate ischemic conditions in the primary cardiac myocyte cultures.…”

Section: Methodsmentioning

confidence: 99%

Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Chanyshev

Shainberg

Isak

et al. 2012

Pharmacological Research

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“…Heart slices were fixed with 0.5% formaldehyde solution in PBS for 5 min, washed in PBS, and placed in an incubation medium containing PBS with 1 mg/mL diaminobenzidine (DAB), 1 mg/mL cytochrome c (type III), and 85 mg/mL sucrose (Shneyvays et al 2003). The slices were incubated in the dark at 37 °C for 1–1.5 h. They were then rinsed with distilled water and coverslipped with glycerol for microscopy and detection of cytochrome c oxidase (COX).…”

Section: Methodsmentioning

confidence: 99%

Involvement of UTP in protection of cardiomyocytes from hypoxic stressThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).

Shainberg

Yitzhaki

Golan

et al. 2009

Can. J. Physiol. Pharmacol.

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Massive amounts of nucleotides are released during ischemia in the cardiovascular system. Although the effect of the purine nucleotide ATP has been intensively studied in myocardial infarction, the cardioprotective role of the pyrimidine nucleotide UTP is still unclear, especially in the cardiovascular system. The purpose of our study was to elucidate the protective effects of UTP receptor activation and describe the downstream cascade for the cardioprotective effect. Cultured cardiomyocytes and left anterior descending (LAD)-ligated rat hearts were pretreated with UTP and exposed to hypoxia–ischemia. In vitro experiments revealed that UTP reduced cardiomyocyte death induced by hypoxia, an effect that was diminished by suramin. UTP caused several effects that could trigger a cardioprotective response: a transient increase of [Ca2+]i, an effect that was abolished by PPADS or RB2; phosphorylation of the kinases ERK and Akt, which was abolished by U0126 and LY294002, respectively; and reduced mitochondrial calcium elevation after hypoxia. In vivo experiments revealed that UTP maintained ATP levels, improved mitochondrial activity, and reduced infarct size. In conclusion, UTP administrated before ischemia reduced infarct size and improved myocardial function. Reduction of mitochondrial calcium overload can partially explain the protective effect of UTP after hypoxic–ischemic injury.

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“…6.1.3. General procedure for the synthesis of N-5-substituted 2-aryl-4,5-dihydro-1,2,4-triazolo[1,5-a]quinoxaline derivatives (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) To a suspension of compounds 32-35 26 (1.2 mmol) and small amounts of the corresponding 4,5-dehydro-derivatives 24-27 in anhydrous dichloromethane (40 mL) and anhydrous pyridine (0.1 mL) kept at 0°C and under nitrogen atmosphere, a solution of the suitable acyl chloride or chloroformates (3.6 mmol) in anhydrous dichloromethane (4.0 mL) was drop by drop added. The reaction was stirred at 0°C for 30 min (compounds [11][12][13][14][15], at room temperature for 1 h (4-5, 7, 9-10), 4 h (compound 8), otherwise at reflux for 3 h (2-3, 6).…”

Section: Chemistrymentioning

confidence: 99%

“…Moreover, additional intracellular pathways have been described to be important for intracellular signal transduction in the adenosine biochemical system. 6,8 The improved understanding of the physiological effects mediated by the A 3 AR and of its biology has provided substantial evidence that this AR subtype is an interesting target for different therapeutic interventions. In particular, A 3 AR antagonists are being investigated for the treatment of glaucoma, asthma, inflammation 9 and cerebral ischemia.…”

Section: Introductionmentioning

confidence: 99%

1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure–affinity relationships and molecular modeling studies

Catarzi¹,

Varano²,

Poli³

et al. 2015

Bioorganic & Medicinal Chemistry

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The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.

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Activation of Adenosine A1 and A3 Receptors Protects Mitochondria during Hypoxia in Cardiomyocytes by Distinct Mechanisms

Cited by 5 publications

References 32 publications

Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Involvement of UTP in protection of cardiomyocytes from hypoxic stressThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).

1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure–affinity relationships and molecular modeling studies

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