AICA ribonucleotide

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AICA ribonucleotide
Aminoimidazole carboxamide ribonucleotide.svg
Preferred IUPAC name
[(2R,3S,4R,5R)-5-(5-Amino-4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
Other names
AICAR, Aminoimidazole carboxamide ribonucleotide, AICA ribonucleotide, ZMP, 5-Amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide
3D model (JSmol)
ECHA InfoCard 100.019.285 Edit this at Wikidata
MeSH AICA+ribonucleotide
  • InChI=1S/C9H15N4O8P/c10-7-4(8(11)16)12-2-13(7)9-6(15)5(14)3(21-9)1-20-22(17,18)19/h2-3,5-6,9,14-15H,1,10H2,(H2,11,16)(H2,17,18,19)/t3-,5-,6-,9-/m1/s1 checkY
  • InChI=1/C9H15N4O8P/c10-7-4(8(11)16)12-2-13(7)9-6(15)5(14)3(21-9)1-20-22(17,18)19/h2-3,5-6,9,14-15H,1,10H2,(H2,11,16)(H2,17,18,19)/t3-,5-,6-,9-/m1/s1
  • O=P(O)(O)OC[C@H]2O[C@@H](n1cnc(C(=O)N)c1N)[C@H](O)[C@@H]2O
Molar mass 338.213 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is an intermediate in the generation of inosine monophosphate. AICAR is an analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity. AICAR has been used clinically to treat and protect against cardiac ischemic injury.[1] The drug was first used in the 1980s as a method to preserve blood flow to the heart during surgery.[2] Currently, the drug has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle.[3]

Mechanism of action[edit]

The nucleoside form of AICAR, acadesine, is an analog of adenosine that enters cardiac cells to inhibit adenosine kinase and adenosine deaminase. It enhances the rate of nucleotide re-synthesis increasing adenosine generation from adenosine monophosphate only during conditions of myocardial ischemia.[4] In cardiac myocytes, acadesine is phosphorylated to AICAR to activate AMPK without changing the levels of the nucleotides.[5] AICAR is able to enter the de novo synthesis pathway for adenosine synthesis to inhibit adenosine deaminase causing an increase in ATP levels and adenosine levels.[6]

Medical use[edit]

A brief period of coronary arterial occlusion followed by reperfusion prior to prolonged ischemia is known as preconditioning. It has been shown that this is protective. Preconditioning preceded myocardial infarction, may delay cell death and allow for greater salvage of myocardium through reperfusion therapy.[7] AICAR has been shown to precondition the heart shortly before or during ischemia.[8] AICAR triggers a preconditioned anti-inflammatory state by increasing NO production from endothelial nitric oxide synthase.[9] When AICAR is given 24 hours prior to reperfusion, it prevents post ischemic leukocyte-endothelial cell adhesive interactions with increased NO production.[10] AICAR-dependent preconditioning is also mediated by an ATP-sensitive potassium channel and hemeoxygenase-dependent mechanism. It increases AMPK-dependent recruitment of ATP-sensitive K channels to the sarcolemma causing the action potential duration to shorten, and preventing calcium overload during reperfusion.[11] The decrease in calcium overload prevents inflammation activation by ROS.[12] AICAR also increases AMPK-dependent glucose uptake through translocation of GLUT-4 which is beneficial for the heart during post-ischemic reperfusion.[13] The increase in glucose during AICAR preconditioning lengthens the period for preconditioning up to 2 hours in rabbits and 40 minutes in humans undergoing coronary ligation.[7][14] As a result, AICAR reduces the frequency and size of myocardial infarcts up to 25% in humans allowing improved blood flow to the heart.[7][15] As well, the treatment has been shown to decrease the risk of an early death and improve recovery after surgery from an ischemic injury.[7]

Use as a performance-enhancing drug[edit]

In 2009, the French Anti-Doping Agency, suspected that AICAR had been used in the 2009 Tour de France for its supposed performance enhancing properties.[16][17] Although a detection method was reportedly given to the World Anti-Doping Agency, it was unknown if this method was implemented.[18] As of January 2011, AICAR was officially a banned substance in the World Anti Doping Code,[19] and the standard levels in elite athletes have been determined, to interpret test results.[20][21]

See also[edit]


  1. ^ Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229:558–565(1995)
  2. ^ Galinanes M, Bullough D, Mullane KM, Hearse DJ. Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart.Circulation 86:589–597 (1992)
  3. ^ Zarembo, Alan. "'Exercise pill' could take the work out of workouts." Los Angeles Times. 01 08 2008, n. pag. Web. 21 Jan. 2012.
  4. ^ Kristiansen, S.B. et al. 5-Aminoimidazole-4-carboxamide-1- β - d -ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre-conditioning : Potential Role of AMP-Activated Protein Kinase. Pharmacology Toxicology 10-16 (2009).doi:10.1111/j.1742-7843.2009.00402.x
  5. ^ Zhang, L., Frederich, M., He, H., & Balschi, J. a. Relationship between 5-aminoimidazole-4-carboxamide-ribotide and AMP-activated protein kinase activity in the perfused mouse heart. American Journal of Physiology. Heart and circulatory physiology, 290(3), .H1235-43. (2006)doi:10.1152/ajpheart.00906.2005
  6. ^ Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol 284:R936–R944 (2003)
  7. ^ a b c d Murry, C.E., Jennings, R.B. & Reimer, K.A.. Preconditioning with ischaemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136. (1986)
  8. ^ Mullane K Acadesine: the prototype adenosine regulating for reducing myocardial ischaemic injury. Cardiovasc Res 27:43–47(1993)
  10. ^ F. Spencer Gaskin, Kazuhiro Kamada, Mozow Yusof, William Durante, Garrett Gross, and Ronald J. Korthuis. AICAR Preconditioning Prevents Postischemic Leukocyte Rolling and Adhesion: Role of KATP Channels and Heme Oxygenase Microcirculation 16:2, 167-176 (2009)
  11. ^ Sukhodub, A., Jovanovic, S., Du, Q., Budas, G., Clelland, A.K., Shen, M., Sakamoto, K., Tian, R. & Jovanovic, A. AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol 210, 224–236. (2007).
  12. ^ Tsuchida, A., Yang, X.M., Burckhartt, B., Mullane, K.M., Cohen, M.V. & Downey, J.M. Acadesine extends the window of protection afforded by ischaemic preconditioning. Cardiovasc Res 28, 379–383. (1994).
  13. ^ Iii, R.R.R. et al. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Society (2012).
  14. ^ Burckhartt, B., Yang, X.M., Tsuchida, A., Mullane, K.M., Downey, J.M. & Cohen, M.V. Acadesine extends the window of protection afforded by ischaemic preconditioning in conscious rabbits. Cardiovasc Res 29, 653–657. (1995).
  15. ^ Mangano DT. Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis Pflügers Arch - Eur J Physiol (2006) 453:147–156 155 of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group. JAMA 277:325–332(1997)
  16. ^ Cooke, Nicole. "CIRC report is admirable but authorities must do more on drugs". The Guardian. Retrieved 13 March 2015. There will always be new drugs, such as the weight-loss drug Aicar, which enables riders to shed up to 7kg and yet still maintain their power output. Obviously, it takes time to develop tests for these but it needs to be agreed that retrospective testing can secure sanctions.
  17. ^ Niiler, Eric. "Doping Spreading to Amateur Cyclists: Report". Discovery. Retrieved 13 March 2015. The commission, formed in 2013 by the sport's governing body, interviewed 174 experts, riders, doctors and team officials. It found a flood of new substances or methods used to enhance blood oxygen capacity include Aicar, Xenon gas, ozone therapy, ITPP, Gas6, Actovegin, various forms of EPO such as CERA, "Eprex", EPO zeta, EPO Retacrit, Neorecormon, and Albumina. Most of these are used to help patients with severe anemia or blood disorders.
  18. ^ "AFLD president suspects new drugs in peloton". Cyclingnews. Future Publishing Unlimited. 27 July 2009. Retrieved 17 March 2012.
  19. ^ "Important changes made to the World Anti-Doping Code". Cyclingnews. Future Publishing Unlimited. 20 December 2010. Retrieved 17 March 2012.
  20. ^ Andreas Thomas; Simon Beuck; Jens Christian Eickhoff; Sven Guddat; Oliver Krug; Matthias Kamber; Wilhelm Schänzer; Mario Thevis (2010), "Quantification of urinary AICAR concentrations as a matter of doping controls", Analytical and Bioanalytical Chemistry, Springer, 396: 2899–2908, doi:10.1007/s00216-010-3560-8
  21. ^ "CYCLING INDEPENDENT REFORM COMMISSION" (PDF). Retrieved 13 March 2015. The core elements to achieve performance enhancement through doping in cycling have remained the same over the years: firstly, increasing the blood’s oxygen carrying capacity, and, secondly, stimulating muscle growth and aiding muscle recovery. Over the years riders have adapted the substances and methods used to achieve these goals in response to: (i) the type of substances available and accessible on the pharmaceutical market (e.g., various EPO generations); (ii) specific drug detection capabilities of laboratories, (e.g., the switch from EPO to blood transfusions or to ozone therapy, or even towards the so-called “oxygen in a pill” in the form of GW1516 and AICAR); and (iii) other anti-doping tools, such as the ABP which has led to micro-dosing (see below).