Cardiovascular effects of the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

Joosen, Marloes J.A.; Bueters, Tjerk; Helden, H.P.M. van

doi:10.1007/s00204-003-0513-4

Cited by 18 publications

(10 citation statements)

References 19 publications

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“…A 1 AR overexpression also improves myocardial tolerance to anoxia reoxygenation, in addition to protecting hearts from ischaemia-reperfusion injury 75 . The cardiovascular effects of the A 1 AR agonist CPA also convey protection against Sarin poisoning 76 .…”

Section: Ischaemiamentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,291

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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Section: Ischaemiamentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,291

1,361

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“…Under inert atmosphere, a suspension of 10 (142 mg, 0.75 mmol, 1.00 equivalent), cyclopentylamine (0.22 mL, 2.25 mmol, 3.00 equiv) in dry n-BuOH (1.50 mL) was refluxed for 4 h. The solvent was evaporated and the resulting crude was purified by flash chromatography (CH 2 Cl 2 -MeOH, 9.7:0.3) to get 12 as a white powder (191 mg, 0.52 mmol, 69%). 6-(3-Aminotetrahydrofuranyl)purine (14). Under inert atmosphere, a suspension of 13 (154 mg, 1.00 mmol, 1.00 equivalent), (R)-3-aminotetrahydrofuran hydrochloride (595 mg, 6.00 mmol, 6.00 equivalent) and LiOH (250 mg, 6.00 mmol, 6.00 equivalent) in EtOH (3.5 mL) was refluxed for 6 h. The solution was evaporated and the residue was purified by flash chromatography (CH 2 Cl 2 -MeOH, 9.3:0.7) to get 14 as a white powder (72 mg, 0.35 mmol, 35%).…”

Section: Chemical Synthesis Of Base Acceptors and Tecadenosonmentioning

confidence: 99%

“…Ribavirin (Virazole ® ) is considered the "gold-standard" in the treatment of hepatitis C in association with pegylated interferon-alpha (IFN-α) [10][11][12][13]. Tecadenoson and its congeners are selective A1 receptor agonists, which have been investigated for their use against arrhythmia and atrial fibrillation [14][15][16]. Cladribine (Litak ® ) has been approved for the treatment of symptomatic tricoleukaemia (hairy-cell leukemia).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Ribavirin, Tecadenoson, and Cladribine by Enzymatic Transglycosylation

et al. 2019

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Despite the impressive progress in nucleoside chemistry to date, the synthesis of nucleoside analogues is still a challenge. Chemoenzymatic synthesis has been proven to overcome most of the constraints of conventional nucleoside chemistry. A purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) has been used herein to catalyze the synthesis of Ribavirin, Tecadenoson, and Cladribine, by a “one-pot, one-enzyme” transglycosylation, which is the transfer of the carbohydrate moiety from a nucleoside donor to a heterocyclic base. As the sugar donor, 7-methylguanosine iodide and its 2′-deoxy counterpart were synthesized and incubated either with the “purine-like” base or the modified purine of the three selected APIs. Good conversions (49–67%) were achieved in all cases under screening conditions. Following this synthetic scheme, 7-methylguanine arabinoside iodide was also prepared with the purpose to synthesize the antiviral Vidarabine by a novel approach. However, in this case, neither the phosphorolysis of the sugar donor, nor the transglycosylation reaction were observed. This study was enlarged to two other ribonucleosides structurally related to Ribavirin and Tecadenoson, namely, Acadesine, or AICAR, and 2-chloro-N6-cyclopentyladenosine, or CCPA. Only the formation of CCPA was observed (52%). This study paves the way for the development of a new synthesis of the target APIs at a preparative scale. Furthermore, the screening herein reported contributes to the collection of new data about the specific substrate requirements of AhPNP.

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“…AK inhibitors are of considerable interest as novel site-and event-specific indirect adenosine receptor agonists. They exhibit potent antinociceptive, anticonvulsive, and anti-inflammatory activity without the limiting cardiovascular side effects exhibited by direct adenosine receptor agonists [4][5][6][7]. Furthermore, the AK of the protozoa Toxoplasma gondii, which is pathogenic in immunocompromised individuals such as patients suffering from AIDS, has been identified as a novel potential chemotherapeutic drug target [8].…”

Section: Introductionmentioning

confidence: 99%

Development of off‐line and on‐line capillary electrophoresis methods for the screening and characterization of adenosine kinase inhibitors and substrates

2006

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Fast and convenient CE assays were developed for the screening of adenosine kinase (AK) inhibitors and substrates. In the first method, the enzymatic reaction was performed in a test tube and the samples were subsequently injected into the capillary by pressure and detected by their UV absorbance at 260 nm. An MEKC method using borate buffer (pH 9.5) containing 100 mM SDS (method A) was suitable for separating alternative substrates (nucleosides). For the CE determination of AMP formed as a product of the AK reaction, a phosphate buffer (pH 7.5 or 8.5) was used and a constant current (95 microA) was applied (method B). The methods employing a fused-silica capillary and normal polarity mode provided good resolution of substrates and products of the enzymatic reaction and a short analysis time of less than 10 min. To further optimize and miniaturize the AK assays, the enzymatic reaction was performed directly in the capillary, prior to separation and quantitation of the product employing electrophoretically mediated microanalysis (EMMA, method C). After hydrodynamic injection of a plug of reaction buffer (20 mM Tris-HCl, 0.2 mM MgCl2, pH 7.4), followed by a plug containing the enzyme, and subsequent injection of a plug of reaction buffer containing 1 mM ATP, 100 microM adenosine, and 20 microM UMP as an internal standard (I.S.), as well as various concentrations of an inhibitor, the reaction was initiated by the application of 5 kV separation voltage (negative polarity) for 0.20 min to let the plugs interpenetrate. The voltage was turned off for 5 min (zero-potential amplification) and again turned on at a constant current of -60 microA to elute the products within 7 min. The method employing a polyacrylamide-coated capillary of 20 cm effective length and reverse polarity mode provided good resolution of substrates and products. Dose-response curves and calculated K(i) values for standard antagonists obtained by CE were in excellent agreement with data obtained by the standard radioactive assay.

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Cardiovascular effects of the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

Cited by 18 publications

References 19 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Synthesis of Ribavirin, Tecadenoson, and Cladribine by Enzymatic Transglycosylation

Development of off‐line and on‐line capillary electrophoresis methods for the screening and characterization of adenosine kinase inhibitors and substrates

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