Nucleotide P2Y1 receptor agonists are in vitro and in vivo prodrugs of A1/A3 adenosine receptor agonists: implications for roles of P2Y1 and A1/A3 receptors in physiology and pathology

Liston, Theodore E.; Hinz, Sonja; Müller, Christa E.; Holstein, Deborah; Wendling, Jay M.; Melton, Roger J.; Campbell, Mary E.; Korinek, William S.; Suresh, R. Rama; Sethre-Hofstad, Dane A.; Gao, Zhan Guo; Tosh, Dilip K.; Jacobson, Kenneth A.; Lechleiter, James D.

doi:10.1007/s11302-020-09732-z

Cited by 20 publications

(32 citation statements)

References 58 publications

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“…The current study demonstrated cerebroprotective efficacy of AST-004, a dual agonist for the human A1R and A3R, 12 in a NHP model of 4-hour transient cerebral ischemia. Compared with vehicle treatment, AST-004 treatment reduced total infarct volume 24 hours and 5 days after MCA occlusion.…”

Section: Discussionsupporting

confidence: 51%

“…There is high sequence homology between NHP and human A1R and A3R, 51 and the affinity of AST-004 for the human A1R and A3R is similar, 12 so it is expected that the calculated receptor occupancy values should be highly similar for both adenosine receptors in the NHP and human brain. On E max plots of effect (%inhibition of lesion volume) versus matrix concentrations or estimated receptor occupancy, a linear relationship was observed across the AST-004 dose regimens used in this study.…”

Section: Discussionmentioning

confidence: 99%

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Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke

Liston¹,

Hama

Boltze

et al. 2022

Stroke

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Background and Purpose: Treatment with A1R/A3R (adenosine A1 and A3 receptor) agonists in rodent models of acute ischemic stroke results in significantly reduced lesion volume, indicating activation of adenosine A1R or A3R is cerebroprotective. However, dosing and timing required for cerebroprotection has yet to be established, and whether adenosine A1R/A3R activation will lead to cerebroprotection in a gyrencephalic species has yet to be determined. Methods: The current study used clinical study intervention timelines in a nonhuman primate model of transient, 4-hour middle cerebral artery occlusion to investigate a potential cerebroprotective effect of the dual adenosine A1R/A3R agonist AST-004. Bolus and then 22 hours intravenous infusion of AST-004 was initiated 2 hours after transient middle cerebral artery occlusion. Primary outcome measures included lesion volume, lesion growth kinetics, penumbra volume as well as initial pharmacokinetic-pharmacodynamic relationships measured up to 5 days after transient middle cerebral artery occlusion. Secondary outcome measures included physiological parameters and neurological function. Results: Administration of AST-004 resulted in rapid and statistically significant decreases in lesion growth rate and total lesion volume. In addition, penumbra volume decline over time was significantly less under AST-004 treatment compared with vehicle treatment. These changes correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy. No relevant changes in physiological parameters were observed during AST-004 treatment. Conclusions: These findings suggest that administration of AST-004 and combined A1R/A3R agonism in the brain are efficacious pharmacological interventions in acute ischemic stroke and warrant further clinical evaluation.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke

Liston¹,

Hama

Boltze

et al. 2022

Stroke

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“…The detailed mechanisms of this P 2X7 R-A 2A R interactions also remain to be unraveled and they can involve different possibilities: one possibility is the formation of heteromers, which has been documented for P 2X7 R (Antonio et al, 2011) and for A 2A R (reviewed in Ferré and Ciruela, 2019) and between different P 2 R and P 1 R (Namba et al, 2010); another possibility is the use of transducing systems of each receptor to control the other receptor function, as has been shown for P 2X7 R controlling metabotropic receptors (reviewed in Miras-Portugal et al, 2019), A 2A R controlling ionotropic receptors (e.g., Garção et al, 2013;Temido-Ferreira et al, 2020) and between different P 2 R and P 1 R (George et al, 2016); a third possibility is a key role of ecto-nucleotidases metabolizing ATP into adenosine in a rapid (Dunwiddie et al, 1997;Cunha et al, 1998) and highly controlled manner (James and Richardson, 1993;Cunha, 2001) to format the balanced activation of both receptors (Kukley et al, 2004;Liston et al, 2020). After this first step establishing an interaction between A 2A R and P 2X7 R, future work will be required to detail the mechanistic basis of this A 2A R-P 2X7 R interaction.…”

Section: Discussionmentioning

confidence: 89%

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

Dias

Lopes

Gonçalves

et al. 2021

Front. Cell. Neurosci.

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Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia “activation”) and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 μM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 μM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.

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“…A 3 AR agonists are under development for treatment of ischemic and inammatory conditions. 16,26,27 We note that 2-alkylthio modications of adenosine have already been well explored for receptor affinity in the ribose series, 30 but not in the (N)-methanocarba series. The receptor affinity of 2-alkyloxo-ether modi-ed adenosine analogues was also studied in detail.…”

Section: Pharmacological Evaluationmentioning

confidence: 91%

“…9,[11][12][13][14] Thus, it is of interest to identify more efficient synthetic approaches that might be adaptable to pharmaceutical development. Here, we compared a linear synthesis of 2methylthio-(N)-methanocarba-adenosine (MRS4322, an A 3 AR agonist with cerebroprotective efficacy) 15,16 with a convergent approach that is designed to increase overall yield and to optimally use the precious [3.1.0]bicyclohexane intermediate. We investigated the generality and scalability of the convergent route to the synthesis of (N)-methanocarba-adenosine derivatives having other C2 position substitution.…”

Section: Introductionmentioning

confidence: 99%

Convergent synthesis of 2-thioether-substituted (N)-methanocarba-adenosines as purine receptor agonists

Suresh

Poe²,

Lin

et al. 2021

RSC Adv.

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Nucleotide P2Y1 receptor agonists are in vitro and in vivo prodrugs of A1/A3 adenosine receptor agonists: implications for roles of P2Y1 and A1/A3 receptors in physiology and pathology

Cited by 20 publications

References 58 publications

Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke

Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

Convergent synthesis of 2-thioether-substituted (N)-methanocarba-adenosines as purine receptor agonists

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