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Research ArticleDrug Discovery and Translational Medicine

Protection from Myocardial Ischemia/Reperfusion Injury by a Positive Allosteric Modulator of the A3 Adenosine Receptor

Lili Du, Zhan-Guo Gao, Kasem Nithipatikom, Adriaan P. IJzerman, Jacobus P. D. van Veldhoven, Kenneth A. Jacobson, Garrett J. Gross and John A. Auchampach
Journal of Pharmacology and Experimental Therapeutics January 2012, 340 (1) 210-217; DOI: https://doi.org/10.1124/jpet.111.187559
Lili Du
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Zhan-Guo Gao
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Kasem Nithipatikom
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Adriaan P. IJzerman
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Jacobus P. D. van Veldhoven
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Kenneth A. Jacobson
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Garrett J. Gross
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John A. Auchampach
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Abstract

Adenosine is increased in ischemic tissues where it serves a protective role by activating adenosine receptors (ARs), including the A3 AR subtype. We investigated the effect of N-{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarboxamide (LUF6096), a positive allosteric modulator of the A3 AR, on infarct size in a barbital-anesthetized dog model of myocardial ischemia/reperfusion injury. Dogs were subjected to 60 min of coronary artery occlusion and 3 h of reperfusion. Infarct size was assessed by macrohistochemical staining. Three experimental groups were included in the study. Groups I and II received two doses of vehicle or LUF6096 (0.5 mg/kg i.v. bolus), one administered before ischemia and the other immediately before reperfusion. Group III received a single dose of LUF6096 (1 mg/kg i.v. bolus) immediately before reperfusion. In preliminary in vitro studies, LUF6096 was found to exert potent enhancing activity (EC50 114.3 ± 15.9 nM) with the canine A3 AR in a guanosine 5′-[γ-[35S]thio]triphosphate binding assay. LUF6096 increased the maximal efficacy of the partial A3 AR agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide and the native agonist adenosine more than 2-fold while producing a slight decrease in potency. In the dog studies, administration of LUF6096 had no effect on any hemodynamic parameter measured. Pretreatment with LUF6096 before coronary occlusion and during reperfusion in group II dogs produced a marked reduction in infarct size (∼50% reduction) compared with group I vehicle-treated dogs. An equivalent reduction in infarct size was observed when LUF6096 was administered immediately before reperfusion in group III dogs. This is the first study to demonstrate efficacy of an A3 AR allosteric enhancer in an in vivo model of infarction.

Footnotes

  • This research was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL077707, R37-HL074314] and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.187559.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    AAR
    area at risk
    ADA
    adenosine deaminase
    AR
    adenosine receptor
    [3H]CGS 21680
    2-[p-(2-carboxyethyl)phenethylamino]-5′-N-[3H]ethylcarboxamidoadenosine
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate
    Cl-IB-MECA
    2-chloro-N6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide
    CP532,903
    (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide
    DU124183
    1H-imidazo[4,5-c]quinolin-4-amine
    [35S]GTPγS
    guanosine 5′-[γ-[35S]thio]triphosphate
    HEK
    human embryonic kidney
    [125I]I-AB-MECA
    N6-(4-amino-3-[125I]iodobenzyl)adenosine-5′-N-methylcarboxamide
    LAD
    left anterior descending
    LC-MS
    liquid chromatography-mass spectroscopy
    LUF6000
    N-(3,4-dichlorophenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-amine)
    LUF6096
    N- {2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarboxamide
    NECA
    adenosine-5′-N-ethylcarboxamide
    PAM
    positive allosteric modulator
    PSB-603
    8-[4-[4-(4-chlorophenyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine.

  • Received August 31, 2011.
  • Accepted October 18, 2011.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 340 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 1
1 Jan 2012
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Research ArticleDrug Discovery and Translational Medicine

LUF6096 and Myocardial Infarction

Lili Du, Zhan-Guo Gao, Kasem Nithipatikom, Adriaan P. IJzerman, Jacobus P. D. van Veldhoven, Kenneth A. Jacobson, Garrett J. Gross and John A. Auchampach
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 210-217; DOI: https://doi.org/10.1124/jpet.111.187559

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Research ArticleDrug Discovery and Translational Medicine

LUF6096 and Myocardial Infarction

Lili Du, Zhan-Guo Gao, Kasem Nithipatikom, Adriaan P. IJzerman, Jacobus P. D. van Veldhoven, Kenneth A. Jacobson, Garrett J. Gross and John A. Auchampach
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 210-217; DOI: https://doi.org/10.1124/jpet.111.187559
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