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Partial adenosine A1 receptor agonists for cardiovascular therapies

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Abstract

Adenosine, a purine nucleoside, is present in all cells in tightly regulated concentrations. It has many different physiological effects in the whole body and in the heart. Adenosine activates four G protein-coupled receptors A1, A2a, A2b, and A3. Activation of myocardial A1 receptors has been shown to inhibit a variety of myocardial pathologies associated with ischemia and reperfusion injury, including stunning, arrhythmogenesis, coronary and ventricular dysfunction, acute myocardial infarction, apoptosis, and chronic heart failure, implying several options for new cardiovascular therapies for diseases, like angina pectoris, control of cardiac rhythm, ischemic injury during an acute coronary syndrome, or heart failure. However, the main issue of using full A1 receptor agonists in such indications is the broad physiologic spectrum of cardiac and extracardiac effects. Desired A1 receptor-mediated protective and regenerative cardiovascular effects might be counter-regulated by unintended side effects when considering full A1 receptor agonists. These effects can be overcome by partial A1 agonists. Partial A1 agonists can be used to trigger only some of the physiological responses of receptor activation depending on endogenous adenosine levels and on receptor reserve in different tissues. CV-Therapeutics reported the identification of a partial A1 receptor agonist CVT-3619, and recently, another partial A1 receptor agonist VCP28 was published. Both compounds are adenosine derivatives. Adenosine-like A1 receptor agonists often have the drawback of a short half-life and low bioavailability, making them not suitable for chronic oral therapy. We identified the first non-adenosine-like partial A1 receptor agonist(s) with pharmacokinetics optimal for oral once daily treatment and characterized the qualities of the partial character of the A1 receptor agonist(s) in preclinical and clinical studies.

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Abbreviations

ACS:

Acute coronary syndrome

CCPA:

2-Chloro-N6-cyclopentyladenosine

CNS:

Central nervous system

References

  1. Linden J (2005) Adenosine in tissue protection and tissue regeneration. Mol Pharmacol 67:1385–1387. doi:10.1124/mol.105.011783

    Article  PubMed  CAS  Google Scholar 

  2. Brodde O-E, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51:651–690

    PubMed  CAS  Google Scholar 

  3. Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 264:527–552

    Google Scholar 

  4. Mustafa SJ, Morrison RR, Teng B, Pelleg A (2009) Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology. Handb Exp Pharmacol 193:161–188. doi:10.1007/978-3-540-89615-9_6

    Article  PubMed  CAS  Google Scholar 

  5. Hussain T, Mustafa SJ (1995) Binding of A1 adenosine receptor ligand [3H]8-cyclopentyl-1,3-dipropylxanthine in coronary smooth muscle. Circ Res 77:194–198

    PubMed  CAS  Google Scholar 

  6. Musser B, Morgan ME, Leid M, Murray TF, Linden J, Vestal RE (1993) Species comparison of adenosine and beta-adrenoceptors in mammalian atrial and ventricular myocardium. Eur J Pharmacol 246:105–111

    Article  PubMed  CAS  Google Scholar 

  7. Van Calker D, Müller M, Hamprecht B (1978) Adenosine inhibits the accumulation of cyclic AMP in cultured brain cells. Nature 276:839–841

    Article  PubMed  Google Scholar 

  8. Londos C, Cooper DMF, Wolff J (1980) Subclasses of external adenosine receptors. Proc Natl Acad Sci U S A 77:2551–2554

    Article  PubMed  CAS  Google Scholar 

  9. Finegan BA, Lopaschuk GD, Gandhi M, Clanachan AS (1996) Inhibition of glycolysis and enhanced mechanical function of working rat hearts as a result of adenosine A1 receptor stimulation during reperfusion following ischaemia. Br J Pharmacol 118:355–363

    PubMed  CAS  Google Scholar 

  10. Peart J, Headrick JP (2000) Intrinsic A(1) adenosine receptor activation during ischemia or reperfusion improves recovery in mouse hearts. Am J Physiol Heart Circ Physiol 279:H2166–H2175

    PubMed  CAS  Google Scholar 

  11. Headrick JP, Hack B, Ashton KJ (2003) Acute adenosinergic cardioprotection in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 285:H1797–H1819. doi:10.1152/ajpheart.00407.2003285/5/H1797

    PubMed  CAS  Google Scholar 

  12. Reichelt ME, Willems L, Molina JG, Sun CX, Noble JC, Ashton KJ, Schnermann J, Blackburn MR, Headrick JP (2005) Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance. Circ Res 96:363–367. doi:10.1161/01.RES.0000156075.00127.C3

    Article  PubMed  CAS  Google Scholar 

  13. Ely SW, Berne RM (1992) Protective effects of adenosine in myocardial ischemia. Circulation 85:893–904

    PubMed  CAS  Google Scholar 

  14. Mubagwa K, Flameng W (2001) Adenosine, adenosine receptors and myocardial protection: an updated overview. Cardiovasc Res 52:25–39

    Article  PubMed  CAS  Google Scholar 

  15. Liao Y, Takashima S, Asano Y, Asakura M, Ogai A, Shintani Y, Minamino T, Asanuma H, Sanada S, Kim J, Ogita H, Tomoike H, Hori M, Kitakaze M (2003) Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. Circ Res 93:759–766. doi:10.1161/01.RES.0000094744.88220.62

    Article  PubMed  CAS  Google Scholar 

  16. Stone TW, Ceruti S, Abbracchio MP (2009) Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handb Exp Pharmacol 193:535–587. doi:10.1007/978-3-540-89615-9_17

    Article  PubMed  CAS  Google Scholar 

  17. Liang BT, Donovan LA (1990) Differential desensitization of A1 adenosine receptor-mediated inhibition of cardiac myocyte contractility and adenylate cyclase activity. Relation to the regulation of receptor affinity and density. Circ Res 67:406–414

    PubMed  CAS  Google Scholar 

  18. Green A (1987) Adenosine receptor down-regulation and insulin resistance following prolonged incubation of adipocytes with an A1 adenosine receptor agonist. J Biol Chem 262:15702–15707

    PubMed  CAS  Google Scholar 

  19. Lee HT, Thompson CI, Hernandez A, Lewy JL, Belloni FL (1993) Cardiac desensitization to adenosine analogues after prolonged R-PIA infusion in vivo. Am J Physiol 265:H1916–H1927

    PubMed  CAS  Google Scholar 

  20. Roman V, Keijser JN, Luiten PG, Meerlo P (2008) Repetitive stimulation of adenosine A1 receptors in vivo: changes in receptor numbers, G-proteins and A1 receptor agonist-induced hypothermia. Brain Res 29:69–74. doi:10.1016/j.brainres.2007.11.044

    Article  Google Scholar 

  21. Srinivas M, Shryock JC, Dennis DM, Baker SP, Belardinelli L (1997) Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes. Mol Pharmacol 52:683–691

    PubMed  CAS  Google Scholar 

  22. Parsons WJ, Stiles GL (1987) Heterologous desensitization of the inhibitory A1 adenosine receptor-adenylate cyclase system in rat adipocytes. Regulation of both Ns and Ni. J Biol Chem 262:841–847

    PubMed  CAS  Google Scholar 

  23. Longabaugh JP, Didsbury J, Spiegel A, Stiles GL (1989) Modification of the rat adipocyte A1 adenosine receptor-adenylate cyclase system during chronic exposure to an A1 adenosine receptor agonist: alterations in the quantity of GS alpha and Gi alpha are not associated with changes in their mRNAs. Mol Pharmacol 36:681–688

    PubMed  CAS  Google Scholar 

  24. Fatholahi M, Xiang Y, Wu Y, Li Y, Wu L, Dhalla AK, Belardinelli L, Shryock JC (2006) A novel partial agonist of the A1-adenosine receptor and evidence of receptor homogeneity in adipocytes. J Pharmacol Exp Ther 317:676–684. doi:10.1124/jpet.105.099119

    Article  PubMed  CAS  Google Scholar 

  25. Dhalla A, Santikul M, Smith M, Wong MY, Shryock J, Belardinelli L (2007) Anti-lipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: comparison with nicotinic acid. J Pharmacol Exp Ther 321:327–333. doi:10.1124/jpet.106.114421

    Article  PubMed  CAS  Google Scholar 

  26. Urmaliya VB, Pouton CW, Devine SM, Haynes JM, Warfe L, Scammelis PJ, White PJ (2010) A novel highly selective adenosine A1 receptor agonist VCP28 reduces ischemia injury in a cardiac cell line and ischemia–reperfusion injury in isolated rat hearts at concentrations that do not affect heart rate. J Cardiovasc Pharmacol 56:282–292. doi:10.1097/FJC.0b013e3181eb8563

    Article  PubMed  CAS  Google Scholar 

  27. Kiesmann WF, Elzain E, Zablocki F (2009) A1 adenosine receptor antagonists, agonists and allosteric enhancers. In: Wilson CN, Mustafa SJ (eds) Handbook of experimental pharmacology 193. Springer, Berlin, pp 25–58

    Google Scholar 

  28. Nell P, Albrecht-Küpper B (2009) The adenosine A1 receptor and its ligands. In: Lawton G, Witty DR (eds) Progress in medicinal chemistry. Elsevier, Amsterdam, pp 164–201. doi:10.1016/S0079-6468(08)00204-X

    Google Scholar 

  29. Lorenzen A, Fuss M, Vogt H, Schwabe U (1993) Measurement of guanine nucleotide-binding protein activation by A1 adenosine receptor agonists in bovine brain membranes: stimulation of guanosine-5′-O-(3[35S]thio)triphosphate binding. Mol Pharmacol 44:115–123

    PubMed  CAS  Google Scholar 

  30. Lorenzen A, Guerra L, Vogt H, Schwabe U (1996) Interaction of full and partial agonists of the a1 adenosine receptor with receptor/G protein complexes in rat brain membranes. Mol Pharmacol 49:915–926

    PubMed  CAS  Google Scholar 

  31. Rosentreter U, Krämer T, Shimada M, Hübsch W, Diedrichs N, Krahn T, Henninger K, Stasch JP, Wischnat R (2003) PCT Int Appl, WO 03 053441 CAN 139:36542

  32. Wu L, Belardinelli L, Zablocki JA, Palle V, Shryock JC (2001) A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts. Am J Physiol 280:H334–H343

    CAS  Google Scholar 

  33. Aderis Pharmaceuticals. Safety and efficacy study of an A1-adenosine receptor agonist to slow heart rate in atrial fibrillation 2005. Available from: http//:www.clinicalstrials.gov./ct/show/NCT00040001?order=1

  34. Bayer Schering Pharma AG (2007) Clinical study in ClinicalTrials.gov identifier NCT00568945. Bayer Schering Pharma AG, Wuppertal

    Google Scholar 

  35. Zablocki JA, Wu L, Shryock JC, Belardinelli L (2004) Partial A1 adenosine receptor agonists from a molecular perspective and their potential use as chronic ventricular rate control agents during atrial fibrillation (AF). Curr Top Med Chem 4:839–854

    Article  PubMed  CAS  Google Scholar 

  36. Otani H (2008) Ischemic preconditioning: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 10:207–247. doi:10.1089/ars.2007.1679

    Article  PubMed  CAS  Google Scholar 

  37. Baxter GF (2002) Role of adenosine in delayed preconditioning of myocardium. Cardiovasc Res 55:483–494

    Article  PubMed  CAS  Google Scholar 

  38. Thornton JD, Liu GS, Olsson RA, Downey JM (1992) Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation 85:659–665

    PubMed  CAS  Google Scholar 

  39. Headrick JP, Lasley RD (2009) Adenosine receptors and reperfusion injury of the heart. Handb Exp Pharmacol 193:189–214. doi:10.1007/978-3-540-89615-9_7

    Article  PubMed  CAS  Google Scholar 

  40. Sommerschild HT, Kirkebøen KA (2002) Preconditioning—endogenous defence mechanisms of the heart. Acta Anaesthesiol Scand 46:123–137

    Article  PubMed  CAS  Google Scholar 

  41. Hausenloy DJ, Yellon DM (2006) Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res 70:240–253. doi:10.1016/j.cardiores.2006.01.017

    Article  PubMed  CAS  Google Scholar 

  42. Dana A, Baxter GF, Walker JM, Yellon DM (1998) Prolonging the delayed phase of myocardial protection: repetitive adenosine A1 receptor activation maintains rabbit myocardium in a preconditioned state. J Am Coll Cardiol 31:1142–1149

    Article  PubMed  CAS  Google Scholar 

  43. Peart JN, Gross GJ (2003) Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol 285:H81–H89. doi:10.1152/ajpheart.00985.200200985.2002

    PubMed  CAS  Google Scholar 

  44. Tendera M, Sosnowski M, Gaszewska-Zurek E, Parma Z, Neuser D, Seman L (2007) The oral adenosine A1 receptor agonist, BAY 68-4986, reduces heart rate at peak exercise in patients with chronic stable angina. J Am Coll Cardiol 49(suppl A):232A

    Google Scholar 

  45. Dhalla AK, Shryock JC, Shreeniwas R, Belardinelli L (2003) Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem 3:369–385

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Raimund Kast and Katja Zimmermann for the data on the 35S-GTP binding assay and the Langendorff heart testing of capadenoson.

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Authors and Affiliations

  1. Research Center Wuppertal, Department of Heart Diseases, Institute of Cardiology, Bayer Pharma AG, Aprather Weg 18a, 42096, Wuppertal, Germany

    Barbara E. Albrecht-Küpper & Kirsten Leineweber

  2. Bayer Healthcare LLC, Global Drug Discovery - US Innovation Center, 455 Mission Bay Blvd South, San Francisco, CA, 94158, USA

    Peter G. Nell

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  1. Barbara E. Albrecht-Küpper
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  3. Peter G. Nell
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Correspondence to Barbara E. Albrecht-Küpper.

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Albrecht-Küpper, B.E., Leineweber, K. & Nell, P.G. Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic Signalling 8 (Suppl 1), 91–99 (2012). https://doi.org/10.1007/s11302-011-9274-3

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