KF24345, an Adenosine Uptake Inhibitor, Suppresses Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production and Leukopenia via Endogenous Adenosine in Mice

Noji, Tohru; Takayama, Makoto; Mizutani, Mirai; Okamura, Yuko; Takai, Haruki; Karasawa, Akira; Kusaka, Hideaki

doi:10.1124/jpet.300.1.200

Cited by 31 publications

(14 citation statements)

References 33 publications

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“…7). These results are compatible with the long duration of action of the compound as an adenosine uptake inhibitor in some animal models (Noji et al, 2002c).…”

Section: Kf24345supporting

confidence: 76%

“…1). These investigators proposed that the anti-inflammatory activity of this compound was due to inhibition of adenosine uptake and metabolism, and that it was more effective than existing agents such as dilazep, dipyridamole, and draflazine due to enhanced bioavailability after oral administration and a longer duration of action in vivo (Noji et al, 2002c). However, these studies did not distinguish between ENT subtypes.…”

mentioning

confidence: 87%

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Interaction of the Novel Adenosine Uptake Inhibitor 3-[1-(6,7-Diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione Hydrochloride (KF24345) with the es and ei Subtypes of Equilibrative Nucleoside Transporters

Hammond

Archer²

2003

J Pharmacol Exp Ther

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Nucleosides such as adenosine, as well as many nucleoside-based drugs, permeate cell membranes via a family of equilibrative nucleoside transporters (ENTs). We assessed the effects of (3-[1-(6,7-diethoxy-2-morpholino-quinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), a novel anti-inflammatory agent that potentiates the actions of adenosine, on the es (inhibitor-sensitive) and ei (inhibitor-resistant) subtypes of ENTs in human, mouse, and rat cells. KF24345 was similar to the prototypical high-affinity inhibitor nitrobenzylthioinosine (NBMPR) for blocking the human es transporter (K I of ϳ0.4 nM), but was 50-fold more effective than NBMPR at blocking the human ei transporter (K I of ϳ100 nM). KF24345 displayed significantly less species heterogeneity in its affinity for the es transporter than did dipyridamole, a widely used inhibitor of nucleoside transport; KF24345 may thus prove useful as an inhibitor for studies of nucleoside metabolism in a range of animal models. Furthermore, KF24345 seemed to act as a noncompetitive inhibitor of both [ 3

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“…7). These results are compatible with the long duration of action of the compound as an adenosine uptake inhibitor in some animal models (Noji et al, 2002c).…”

Section: Kf24345supporting

confidence: 76%

mentioning

confidence: 87%

Interaction of the Novel Adenosine Uptake Inhibitor 3-[1-(6,7-Diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione Hydrochloride (KF24345) with the es and ei Subtypes of Equilibrative Nucleoside Transporters

Hammond

Archer²

2003

J Pharmacol Exp Ther

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“…Moreover, effects of adenosinergic stimuli vary across experimental models. Augmented endogenous adenosine (via inhibition of cellular uptake) reduces TNF-α levels and leukopenia in an A 2 AR-dependent manner in male ddY mice [17]. In contrast, exogenous adenosine does not alter mortality or TNF-α levels in the LPS treated females of the CF1 mouse strain, though a related nucleoside analogue reduces both [18].…”

Section: Introductionmentioning

confidence: 99%

The adenosine A2A receptor — Myocardial protectant and coronary target in endotoxemia

Reichelt

Ashton

Tan

et al. 2013

International Journal of Cardiology

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Background Cardiac injury and dysfunction are contributors to disease progression and mortality in sepsis. This study evaluated the cardiovascular role of intrinsic A2A adenosine receptor (A2AAR) activity during lipopolysaccharide (LPS)-induced inflammation. Methods We assessed the impact of 24 h of LPS challenge (20 mg/kg, IP) on cardiac injury, coronary function and inflammatory mediator levels in Wild-Type (WT) mice and mice lacking functional A2AARs (A2AAR KO). Results Cardiac injury was evident in LPS-treated WTs, with ∼7-fold elevation in serum cardiac troponin I (cTnI), and significant ventricular and coronary dysfunction. Absence of A2AARs increased LPS-provoked cTnI release at 24 h by 3-fold without additional demise of contraction function. Importantly, A2AAR deletion per se emulated detrimental effects of LPS on coronary function, and LPS was without effect in coronary vessels lacking A2AARs. Effects of A2AAR KO were independent of major shifts in circulating C-reactive protein (CRP) and haptoglobin. Cytokine responses were largely insensitive to A2AAR deletion; substantial LPS-induced elevations (up to 100-fold) in IFN-γ and IL-10 were unaltered in A2AAR KO mice, as were levels of IL-4 and TNF-α. However, late elevations in IL-2 and IL-5 were differentially modulated by A2AAR KO (IL-2 reduced, IL-5 increased). Data demonstrate that in the context of LPS-triggered cardiac and coronary injury, A2AAR activity protects myocardial viability without modifying contractile dysfunction, and selectively modulates cytokine (IL-2, IL-5) release. A2AARs also appear to be targeted by LPS in the coronary vasculature. Conclusions These experimental data suggest that preservation of A2AAR functionality might provide therapeutic benefit in human sepsis.

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“…This is direct evidence that systemically administered nucleoside transport inhibitors have antinociceptive properties in vivo. Nucleoside transport inhibitors enhance extracellular levels of adenosine by blocking adenosine reuptake into cells, which is reported to be one of the key mechanisms by which adenosine is cleared from the extracellular space 36. The high local turnover of adenosine during states of inflammation37 makes this condition ideally suited for testing the effects of nucleoside transport inhibition.…”

Section: Discussionmentioning

confidence: 99%

Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs

Maes¹,

Pype²,

Hoffmann³

et al. 2012

JPR

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Background and methodsThe role of the endogenous purine nucleoside, adenosine, in nociception is well established. Inhibition of the equilibrative nucleoside transporter (ENT1) prevents adenosine uptake into cells, and could therefore enhance the antinociceptive properties of adenosine. The effects of ENT1 inhibition were studied in two animal models of inflammatory pain. Analgesic activity was assessed in a complete Freund’s adjuvant (CFA)-induced and carrageenan-induced mechanical and thermal hyperalgesia model in the guinea pig.ResultsDraflazine, dipyridamole, dilazep, lidoflazine, soluflazine, and KF24345 showed efficacy in the CFA thermal hyperalgesia model. Draflazine, the most potent compound in this test, was further characterized in the CFA model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia, where it completely reversed the hypersensitivity. The antihyperalgesic effects of draflazine (10 mg/kg, administered subcutaneously) were attenuated by the A1 receptor antagonist, cyclopentyltheophylline (5–40 mg/kg, administered intraperitoneally), by the nonselective adenosine antagonist, caffeine (10–40 mg/kg intraperitoneally), and by the A2 antagonist, DMPX (10 mg/kg administered intraperitoneally).ConclusionENT1 inhibition is an effective way of reversing mechanical and thermal inflammatory hyperalgesia in the guinea pig, and these effects are mediated by enhancement of endogenous adenosine levels. Both A1 and A2 adenosine receptor subtypes are likely to be involved.

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KF24345, an Adenosine Uptake Inhibitor, Suppresses Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production and Leukopenia via Endogenous Adenosine in Mice

Cited by 31 publications

References 33 publications

Interaction of the Novel Adenosine Uptake Inhibitor 3-[1-(6,7-Diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione Hydrochloride (KF24345) with the es and ei Subtypes of Equilibrative Nucleoside Transporters

Interaction of the Novel Adenosine Uptake Inhibitor 3-[1-(6,7-Diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione Hydrochloride (KF24345) with the es and ei Subtypes of Equilibrative Nucleoside Transporters

The adenosine A2A receptor — Myocardial protectant and coronary target in endotoxemia

Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs

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