Adenosine (ADO) is an inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibitors of the ADO-metabolizing enzyme adenosine kinase (AK) may have therapeutic potential as analgesic and anti-inflammatory agents. ABT702 2HCl is a novel and potent non-nucleoside AK inhibitor with an IC50 value of 0.7 nM. It has oral activity in animal models of inflammation and pain. ABT702 was equipotent (IC50 = 1.5 ± 0.3 nM) in inhibiting native human AK (placenta), two human recombinant isoforms (AKlong and AKshort), and AK from monkey, dog, rat, and mouse brain. ABT702 is orally active and fully efficacious in reducing acute somatic nociception (ED50 = 8 μmol/kg i.p.; 65 μmol/kg p.o.) in the mouse hot-plate assay. ABT702 also dose dependently reduced nociception in the phenyl-p-quinone-induced abdominal constriction assay[1]. Significant regional hypometabolism was detected of ABT702 (3 mg/kg; intraperitoneal injection) treated rats, relative to vehicle-treated rats[2].
ABT-702 2HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
H9c2 cells
1 µM
12 hours hypoxia/4 hours reoxygenation
To evaluate the effect of ABT-702 on H/R-induced apoptosis and necroptosis. Results showed that ABT-702 pre-treatment significantly reduced H/R-induced apoptosis and necroptosis in H9c2 cells.
J Cell Mol Med. 2021 Mar;25(6):2931-2943.
HepG2 cells
30 µM
14-24 hours hypoxia followed by 4-24 hours re-oxygenation
To evaluate the effect of ABT-702 on the protective effects of adenosine and inosine under hypoxia and re-oxygenation conditions. Results showed that ABT-702 significantly reversed the protective effects of both adenosine and inosine.
Int J Mol Med. 2013 Feb;31(2):437-46.
C6 rat glioma cells
0.1 µM
24 hours or 48 hours
To evaluate the inhibitory effect of ABT-702 on adenosine kinase and its impact on MTX-mediated cytotoxicity. Results showed that ABT-702 alone did not affect C6 cell viability and failed to alter the cytotoxic effect of MTX.
Purinergic Signal. 2021 Jun;17(2):273-284.
Human coronary arterioles
0.1 µM
30 minutes
To evaluate the effect of ABT-702 on conducted vasodilation in HFpEF patients, results showed that ABT-702 significantly augmented conducted vasodilation in HFpEF patients
Circ Heart Fail. 2019 Aug;12(8):e005762.
Rat gracilis skeletal muscle arteries
0.1 µM
30 minutes
To evaluate the effect of ABT-702 on conducted vasodilation, results showed that ABT-702 significantly augmented conducted vasodilation in obese ZSF1 rats
Circ Heart Fail. 2019 Aug;12(8):e005762.
Human glomerular endothelial cells (HGECs)
50 µM
5 days
To evaluate the effects of ABT702 on glomerular permeability, barrier function, and inflammation in human glomerular endothelial cells under high glucose conditions. ABT702 significantly reduced high glucose-induced elevation in FITC-dextran permeability and MAPK phosphorylation and restored the decrease in occludin expression.
Pharmacol Res. 2014 Jul;85:45-54.
Rat astrocytes
10 µM
60 minutes
ABT-702 completely prevented the adenosine-accelerated ATP restoration
Neurochem Res. 2024 Nov 16;50(1):13.
ABT-702 2HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Spinal nerve ligation (L5/L6) and carrageenan inflammation model
Subcutaneous injection
0.1, 1 and 10 mg/kg
Tests every 10 min for 60 min per dose
To investigate the effect of ABT-702 on spinal neurons in inflammatory and neuropathic pain models. Results showed that ABT-702 significantly inhibited postdischarge, wind-up, and C-fibre evoked responses in spinal neurons, with greater inhibition observed in the nerve injury model.
Br J Pharmacol. 2001 Apr;132(7):1615-23
C57BL/6 mice
Streptozotocin-induced diabetes model
Intraperitoneal injection
1.5 mg/kg
Twice a week for 8 weeks
To evaluate the protective effects of ABT702 on renal inflammation and oxidative stress in diabetic mice. ABT702 significantly reduced blood glucose levels, albuminuria, markers of glomerular injury (nephrinuria and podocalyxin excretion), NADPH oxidase activity, TBARS excretion, renal macrophage infiltration, NF-κB activation, and MCP-1 excretion, while increasing eNOS expression and nitrate/nitrite excretion in diabetic mice.
Pharmacol Res. 2014 Jul;85:45-54.
Obese ZSF1 rats
HFpEF model
Intraperitoneal injection
1.5 mg/kg
Twice a week for eight weeks
To evaluate the effect of ABT-702 on LV diastolic function, results showed that ABT-702 prevented LV diastolic dysfunction and improved conducted vasodilation and LV diastolic function
Circ Heart Fail. 2019 Aug;12(8):e005762.
C57BL/6J mice
Age-related hearing loss model
Intraperitoneal injection
1.5 mg/kg
Twice a week for 6 months or 3 months
To evaluate the protective effect of ABT-702 on age-related hearing loss. Results showed that ABT-702 treatment significantly reduced ABR threshold shifts at 10 and 16 kHz and increased hair cell survival in the apical region of the cochlea.
Exp Gerontol. 2011 Nov;46(11):905-14
C57BL/6 mice
Myocardial ischemia/reperfusion injury model
Intraperitoneal injection
2 mg/kg
Single dose, sustained for 30 minutes ischemia/4 or 24 hours reperfusion
To evaluate the protective effect of ABT-702 on myocardial ischemia/reperfusion injury. Results showed that ABT-702 significantly reduced myocardial infarct size, improved cardiac function, and reduced cell apoptosis and necroptosis.
J Cell Mol Med. 2021 Mar;25(6):2931-2943.
Sprague-Dawley rats
Cocaine sensitization model
Intra-NAc microinjection
2.5 ng/side or 5 ng/side
Single administration, observed for 2 hours
ABT-702 dose-dependently blocked the expression of cocaine sensitization while having no effects on acute cocaine sensitivity, suggesting that upregulation of endogenous adenosine in the accumbens is sufficient to non-selectively stimulate adenosine receptors and reverse the expression of cocaine sensitization.
Neuropharmacology. 2012 Nov;63(6):1172-81
Mice
WT C57BL/6 mice and Adk-tg transgenic mice
Intraperitoneal injection
2.5, 5, and 10 mg/kg
Single administration
To evaluate the antipsychotic-like activity of ABT-702 in normal mice and to reverse apomorphine-induced PPI disruption. ABT-702 enhanced basal PPI and reversed apomorphine-induced PPI disruption.
J Clin Invest. 2012 Jul;122(7):2567-77
Sprague-Dawley rats
Chronic constriction injury (CCI) model
Intraperitoneal injection
5 mg/kg
Single dose
ABT-702 produces powerful analgesic effects in rodent models of experimental neuropathic pain by increasing endogenous adenosine levels through selective adenosine kinase inhibition, mediated via the A3 adenosine receptor (A3AR) signaling pathway.
Brain. 2015 Jan;138(Pt 1):28-35
C57BL/6 mice
Chronic constriction injury (CCI) model
Intraperitoneal injection
5 mg/kg
Single dose
ABT-702 produces powerful analgesic effects in rodent models of experimental neuropathic pain by increasing endogenous adenosine levels through selective adenosine kinase inhibition, mediated via the A3 adenosine receptor (A3AR) signaling pathway.
搜索
