Human Endogenous Metabolite; Microbial Metabolite
Adenosine activates four adenosine receptors (ARs): A1AR, A2AAR, A2BAR, and A3AR.
A1AR: EC50 between 10 nM to 1 μM (activation leads to attenuation of intracellular cAMP).
A2AAR: EC50 between 10 nM to 1 μM (activation elevates intracellular cAMP).
A2BAR: EC50 of 24 μM (activation elevates intracellular cAMP; requires adenosine levels exceeding 10 μM, mainly achieved during pathophysiological conditions).
A3AR: EC50 between 10 nM to 1 μM (activation attenuates intracellular cAMP). [3]

Adenine nucleosides act on four G protein-coupled receptors: one of them, A1 and A3, is mainly coupled to the Gi family G proteins; two of them, A2A and A2B, are mainly coupled to G proteins. These receptors include coffee Antagonist due to entrance of xanthine. Through these receptors, it affects many cells and organs, often with cytoprotective functions [2]. Adenosine is an extracellular signaling molecule generated from its precursor molecules 5'-adenosine triphosphate (ATP)) and 5'-adenosine monophosphate (AMP) [3]. Adenosine is a common metabolite of ATP that exhibits cytotoxic effects at high concentrations. Adenosine (1.0- 4.0 mM; 12-24 hours) inhibits cell viability and triggers endoplasmic reticulum depletion in HepG2 cells [4]. Adenosine induces a variety of phosphates. Adenosine (2.0 mM; 12-24 hours) Induces freedom in HepG2 cells In the HepG2 cell line, successful adenosine-induced activation of AMPK/mTOR partially blocks the ER and reduces inactivated cell death [4].

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Adenosine functions as a platelet aggregation inhibitor. [3]
Adenosine-mediated bradycardia occurs via activation of A1AR. [3]
Arterial vasodilatation and inhibition of platelet aggregation occur via activation of A2AAR. [3]
Ischemic preconditioning of different organs occurs via activation of A2BAR. [3]
Rodent mast-cell degranulation occurs through A3AR-dependent attenuation of intracellular cAMP. [3]
In endothelial cells, activation of adenosine receptors leads to a barrier resealing response following neutrophil transmigration. [3]
In vitro studies of endothelial permeability using small-interfering-RNA-mediated repression of A2BAR selectively increased endothelial leak in response to hypoxia. [3]

Intravenous adenosine causes a temporary heart block and slowing of heart rate. In patients treated with a rapid intravenous bolus, the adenosine-induced heart block typically lasts for only 5-10 seconds due to swift decline of plasma adenosine concentrations. [3]
Intravenous adenosine is used to treat supraventricular tachycardia in perioperative settings; it is among the most frequently used anti-arrhythmic medications in anesthesiology practice. [3]
Adenosine-induced transient cardiac arrest is used to assist accurate deployment of vascular stent grafts in major blood vessels. [3]
In human volunteers exposed to moderate hypoxia (oxygen saturation of 80% over 20 min), plasma adenosine levels increased from approximately 20 nM to over 50 nM. [3]
In mice deficient in extracellular adenosine generation (cd39-/- or cd73-/- mice), ischemia-induced increases in cardiac or renal adenosine levels were similar to un-preconditioned wild-type mice, indicating that extracellular adenosine levels are dramatically elevated with preconditioning (about 5-fold increase). [3]
Adenosine-deaminase-deficient mice have dramatically increased extracellular adenosine levels and die within weeks after birth from severe respiratory distress due to pulmonary adenosine toxicity. [3]

Absorption, Distribution and Excretion
Data on Adenanthin absorption are not yet clear. Adenanthin is primarily excreted in the urine as uric acid. Data on the volume of distribution of Adenanthin are not yet clear. Data on Adenanthin clearance are not yet clear. Intravenously administered Adenanthin is rapidly cleared from the bloodstream primarily through cellular uptake by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, non-concentrated, and bidirectionally symmetrical. Since activation or inactivation of Adenanthin cyclase (Adenocard) does not require hepatic or renal function, hepatic or renal failure is not expected to affect its efficacy or tolerability. Metabolism/Metabolites Adenanthin can be phosphorylated by Adenanthin kinase to Adenanthin monophosphate (ATP). ATP is subsequently rephosphorylated by Adenanthin kinase 1 to Adenanthin diphosphate (ATP), which is then phosphorylated by nucleoside diphosphate kinase A or B to Adenanthin triphosphate (ATP). Additionally, Adenanthin can be deaminated by Adenanthin deaminase to inosine. Inosine is phosphorylated by purine nucleoside phosphorylase to produce hypoxanthine. Hypoxanthine is then oxidized twice by xanthine dehydrogenase to produce the metabolite xanthine, which is subsequently converted into uric acid. Intracellular Adenanthin can be rapidly metabolized through two pathways: one is phosphorylation by Adenanthin kinase to produce Adenanthin monophosphate (ATP); the other is deamination by Adenanthin deaminase in the cytosol to produce inosine. Because the Km and Vmax of Adenanthin kinase are both lower than those of Adenanthin deaminase, deamination only plays an important role when the cytosol Adenanthin is saturated with phosphorylation. Adenanthin is rapidly metabolized intracellularly into inactive metabolites Adenanthin monophosphate (ATP) and inosine… This drug is mainly cleared through cellular uptake, primarily by erythrocytes and vascular endothelial cells via a specific transmembrane nucleoside transport system. The inosine produced by Adenanthin deamination can leave the cell intact or be degraded into hypoxanthine and xanthine, ultimately converting into uric acid. The ATP produced by Adenanthin phosphorylation is integrated into the high-energy phosphate pool. Extracellular Adenanthin is primarily cleared through cellular uptake, but excess Adenanthin may be deaminated by extracellular Adenanthin deaminase. Intracellular Adenanthin is rapidly metabolized via two pathways: phosphorylation by Adenanthin kinase to Adenanthin monophosphate (ATP); and deamination by Adenanthin deaminase in the cytosol to inosine. Half-life: less than 10 seconds. Biological half-life: The half-life of Adenanthin in blood is less than 10 seconds. The half-life of Adenanthin in plasma is less than 10 seconds.

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The short half-life of adenosine is critical for its clinical use; following intravenous bolus, the heart block terminates due to swift decline of plasma adenosine concentrations, typically lasting only 5-10 seconds. [3]
The main mechanism for fast decline of vascular adenosine levels is uptake from extracellular to intracellular compartment via equilibrative nucleoside transporters (ENT1 and ENT2), followed by rapid intracellular metabolism. [3]
Under physiological conditions, typical adenosine concentrations remain lower than 1 μM. Following hypoxia exposure (moderate hypoxia, 20 min), human plasma adenosine levels increased from approximately 20 nM to over 50 nM. In ischemic hearts or kidneys, adenosine tissue concentrations increase approximately 5-fold. [3]
Intracellular adenosine is rapidly metabolized either by adenosine deaminase (conversion to inosine) or by adenosine kinase (conversion to AMP). [3]

Toxicity Summary
Adenanthin slows atrioventricular nodal conduction time and blocks the atrioventricular nodal reentry pathway, thereby restoring normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT with Wolff-Parkinson-White syndrome. This effect is likely mediated by activation of cell surface A1 and A2 Adenanthin receptors. Adenanthin also inhibits slow inward calcium currents and activation of adenylate cyclase in smooth muscle cells, leading to vascular smooth muscle relaxation. Adenanthin increases blood flow in normal coronary arteries, while providing little or no increase in blood flow to stenotic arteries, resulting in a relative difference in thallium chloride (T1201) uptake between myocardium supplied by normal coronary arteries and myocardium supplied by stenotic coronary arteries. Protein Binding Adenanthin binds to albumin in plasma, but data on the extent of binding are unclear.

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Interactions
Methylxanthine drugs (such as caffeine and theophylline) can antagonize the effects of Adenanthin. In the presence of these methylxanthine drugs, a larger dose of Adenanthin may be required, or Adenanthin may be ineffective.
Dapidamox can enhance the effects of Adenanthin. Therefore, in the presence of dipyridamole, a smaller dose of Adenanthin may be effective.
Carbamazepine has been reported to exacerbate atrioventricular block induced by other drugs. Since the primary function of Adenanthin is to reduce atrioventricular node conduction, the presence of carbamazepine may result in more severe atrioventricular block.

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Non-human toxicity values
Intraperitoneal LD50 in mice: 500 mg/kg

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Genetic deletion of adenosine deaminase in mice is associated with dramatic increases in extracellular adenosine levels and a phenotype characterized by pulmonary adenosine toxicity, leading to severe respiratory distress and death within weeks after birth. [3]
Long-term use of adenosine receptor agonists may be associated with fibrotic changes of the liver or the lungs, which may limit these drugs to short-term use in an acute setting. [3]

[1]. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 2007;14(7):1315-1323.

[2]. Pharmacology of Adenosine Receptors: The State of the Art. Physiol Rev. 2018;98(3):1591-1625.

[3]. Adenosine: an old drug newly discovered. Anesthesiology. 2009;111(4):904-915.

[4]. Inhibition of autophagy enhances adenosine induced apoptosis in human hepatoblastoma HepG2 cells. Oncol Rep. 2019;41(2):829-838.

Therapeutic Uses
Analgesics; Antiarrhythmics; Vasodilators. Intravenous adenosylmethketone (Adenocard) is indicated for the conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm, including PSVT associated with accessory pathways (extracorporeal membrane oxygenation syndrome). When clinically necessary, appropriate vagal stimulation (e.g., Valsalva maneuver) should be attempted before administering adenosylmethketone. /US Product Label Includes/ Adenosylmethketone cannot convert atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm. In the presence of atrial flutter or atrial fibrillation, a transient, mild bradycardia may occur immediately after administration of adenocard. For patients unable to exercise adequately, intravenous adenosylmethketone may be used as adjunctive therapy to thallium-201 myocardial perfusion imaging. /US Product Label Includes/
/Experimental Treatment:/...Studies have shown that Adenanthin can improve androgenetic alopecia in Japanese men by thickening thinning hair through follicle atrophy. To investigate the efficacy and safety of Adenanthin treatment in improving female pattern baldness, this study recruited 30 Japanese women with female pattern baldness in a double-blind, randomized, placebo-controlled trial. Volunteers applied either 0.75% Adenanthin lotion or a placebo lotion topically twice daily for 12 months. Efficacy was assessed by dermatologists, researchers, and hair growth charts. Results showed that, based on self-assessment by dermatologists, researchers, and patients, Adenanthin was significantly more effective than placebo. Adenanthin significantly increased the growth rate and thickening rate of hair in the anagen phase. No side effects were observed during the trial. Adenanthin improved hair loss in Japanese women by stimulating hair growth and thickening the hair shaft. Adenanthin can be used to treat female pattern baldness and androgenetic alopecia in men.

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Drug Warnings
Contraindications include known hypersensitivity to Adenanthin, second- or third-degree atrioventricular block (except in patients with implanted functional pacemakers), sinoatrial node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with implanted functional pacemakers), and known or suspected bronchoconstrictive or bronchospasmodic lung disease (e.g., asthma).
After intravenous administration of Adenanthin, new arrhythmias (ventricular premature beats [VPC], atrial premature beats, atrial fibrillation, sinus bradycardia, sinus tachycardia, missed beats, and varying degrees of atrioventricular block) often occur upon restoration of normal sinus rhythm. These arrhythmias usually last only a few seconds and resolve spontaneously without intervention. However, transient or sustained cardiac arrest has been reported after intravenous administration of Adenanthin, sometimes even life-threatening. Ventricular fibrillation has been rarely reported after intravenous administration of this drug, including cases of successful resuscitation and death. In most cases, these adverse reactions occur in patients receiving digoxin concurrently, or less frequently in patients receiving digoxin and verapamil concurrently, although a causal relationship has not been established. Some clinicians have noted that Adenanthin should not be used in patients with wide QRS complex tachycardia of unknown etiology due to the risk of inducing potentially serious arrhythmias, such as atrial fibrillation with a rapid ventricular rate or sustained cardiac arrest with severe hypotension in pre-excitation tachycardia (e.g., atrial flutter). This drug may also induce ventricular fibrillation in patients with severe coronary artery disease. Appropriate resuscitation measures should be readily available. For more complete data on drug warnings for Adenanthin (16 in total), please visit the HSDB record page.

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Pharmacodynamics
Adenanthin can be used as an adjunct to thallium-201 in myocardial perfusion imaging and for sinus rhythm conversion in paroxysmal supraventricular tachycardia. Adenanthin has a short duration of action, with a half-life of <10 seconds, but a wide therapeutic window. Patients should be informed of the risks of cardiovascular side effects, bronchoconstriction, seizures, and allergic reactions.

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Adenosine is an endogenous distress molecule with profound impact on immune response and adaptation to limited oxygen availability (hypoxia). [3]
Extracellular adenosine mainly serves as a signaling molecule and its biological functions occur through activation of adenosine receptors localized on the extracellular surface of cell membranes. [3]
During conditions of cellular distress (inflammation, hypoxia, acute injury), extracellular adenosine stems from phosphoester hydrolysis of its precursor molecules ATP, ADP, or AMP via the ecto-apyrase CD39 and 5'-ecto-nucleotidase CD73. [3]
Hypoxia-inducible factor (HIF) coordinates transcriptional changes that enhance extracellular adenosine signaling: induction of CD39, CD73, and A2BAR expression, repression of equilibrative nucleoside transporters (ENT1/ENT2) and adenosine kinase, leading to increased adenosine levels and signaling. [3]
Adenosine has been implicated in diverse clinical applications: anti-arrhythmic agent, arterial vasodilator (e.g., dipyridamole used during stress-echocardiography to enhance vascular adenosine levels), and platelet aggregation inhibitor (e.g., extended-release dipyridamole in combination with aspirin for prevention of recurrent stroke). [3]
Caffeine (non-specific adenosine receptor antagonist) is suggested for prevention or treatment of postural puncture headache and caffeine withdrawal headache in perioperative patients. [3]
Theophylline (non-specific adenosine receptor antagonist) was used for obstructive airway disease but has been replaced by inhaled long-acting beta-agonist bronchodilators. [3]

C10H13N5O4

267.2413

267.096

C, 44.94; H, 4.90; N, 26.21; O, 23.95

58-61-7

Adenosine-13C5; 159496-13-6; (R)-3-Hydroxybutanoic acid-13C2 sodium; 202114-54-3; Adenosine-1′-13C; 201996-55-6; Adenosine-13C; 54447-57-3; Adenosine-d2; 82741-17-1; Adenosine 5'-diphosphate disodium; 16178-48-6; Adenosine-d; 109923-50-4; Adenosine-15N5; 168566-57-2; Adenosine-2′-13C; 714950-52-4; Adenosine-3′-13C; 714950-53-5; Adenosine-d-1; 119540-53-3; Adenosine-d-2; Adenosine-13C10,15N5; 202406-75-5

60961

White to off-white solid powder

2.1±0.1 g/cm3

676.3±65.0 °C at 760 mmHg

234-236ºC

362.8±34.3 °C

0.0±2.2 mmHg at 25°C

1.907

-1.02

4

8

2

19

335

4

O1[C@]([H])(C([H])([H])O[H])[C@]([H])([C@]([H])([C@]1([H])N1C([H])=NC2=C(N([H])[H])N=C([H])N=C12)O[H])O[H]

OIRDTQYFTABQOQ-KQYNXXCUSA-N

InChI=1S/C10H13N5O4/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(18)6(17)4(1-16)19-10/h2-4,6-7,10,16-18H,1H2,(H2,11,12,13)/t4-,6-,7-,10-/m1/s1

(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol

NSC627048; NSC-627048; Adenosine; NSC 627048

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 27~33.3 mg/mL (101.0~124.7 mM)

Solubility in Formulation 1: 6.67 mg/mL (24.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)