Synthesis and coronary vasodilating activity of 2-substituted adenosines.

Marumoto, Ryuji; Yoshioka, Y.; Miyashita, Osamu; Shima, S.; Imai, K.; Kawazoe, K; Honjo, Mikio

doi:10.1248/cpb.23.759

Cited by 46 publications

(17 citation statements)

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“…Fresh bovine liver was obtained from a local slaughterhouse in Cologne, Germany. [2, H]Adenosine (33.10 Ci/mmol) was obtained from PerkinElmer Life Sciences (Rodgau-Jügesheim, Germany) 2-Substituted adenosine derivatives 2-8 were synthesized in analogy to published procedures [31].…”

Section: Reagents and Chemicalsmentioning

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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Section: Reagents and Chemicalsmentioning

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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“…Thus, adeno sine derivatives with non-vasoselective prop erties developed so far were not suitable for use as antihypertensive drugs. In attempts to develop vasoselective or A2 selective adeno sine derivatives, chemical modifications of adenosine in the N6, 2 or 5'-position have already been documented (10)(11)(12). However, the clinical evaluation of their therapeutic potential has not been established.…”

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confidence: 99%

Pharmacological Profile of the 2-Alkynyladenosine Derivative 2-Octynyladenosine (YT-146) in the Cardiovascular System

Kogi

Uchibori

Aihara

et al. 1991

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the cardiovascular effects of 2-octynyladenosine (YT 146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4,ug/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at hypotensive doses. Orally given YT-146 (0.1-1 mg/kg) produced a potent and long-lasting anti hypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadeno sine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long acting hypotensive agent having less cardiac depressant activity. Adenosine receptors mediate a great variety of biological responses in non-excitable and excitable tissues (1). Two subtypes of adeno sine receptors have been identified, i.e., A, and A2 adenosine receptors, which mediate in hibition and stimulation of adenylate cyclase, respectively (2, 3). In the cardiovascular sys tem, it has been established that the hypoten sive action of adenosine occurs via two differ ent mechanisms, i.e., A2 receptor-mediated vasodilation (4-6) and A, receptor-mediated cardiac depression (7-9). Adenosine deriva tives synthesized so far retain the two mecha nisms of action of adenosine. The cardiode pressant action is by no means acceptable in the treatment of hypertension. Thus, adeno sine derivatives with non-vasoselective prop erties developed so far were not suitable for use as antihypertensive drugs. In attempts to develop vasoselective or A2 selective adeno

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“…[16,17] The first structure-activity studies pointed out that chemical modification of adenosine at the N6, 2-, or 5'-position increases the duration of coronary vasodilating activity, but it reduces potency with the exception of 2-chloroadenosine (2-ClAdo, 2). [18] Starting from these observations, a series of adenosine derivatives substituted at the 2-position with alkoxy, alkyl, amino, and mercapto groups were reported by Marumoto et al [19] 2-Phenylaminoadenosine (CV-1808, 3, Figure 1) proved to be the most potent compound in the series, also endowed with longer duration of effect than that of 2-chloroadenosine.…”

Section: Structure-activity Relationships Of a 2a Adenosine Receptor mentioning

confidence: 95%

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

et al. 2007

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Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.

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Synthesis and coronary vasodilating activity of 2-substituted adenosines.

Cited by 46 publications

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

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

Pharmacological Profile of the 2-Alkynyladenosine Derivative 2-Octynyladenosine (YT-146) in the Cardiovascular System

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

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Synthesis and coronary vasodilating activity of 2-substituted adenosines.

Cited by 46 publications

References 0 publications

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

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

Pharmacological Profile of the 2-Alkynyladenosine Derivative 2-Octynyladenosine (YT-146) in the Cardiovascular System

Highlights on the Development of A2A Adenosine Receptor Agonists and Antagonists

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Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists