Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

Author(s): Sumit Jamwal, Ashish Mittal, Puneet Kumar*, Dana M. Alhayani and Amal Al-Aboudi

Volume 25, Issue 26, 2019

Page: [2892 - 2905] Pages: 14

DOI: 10.2174/1381612825666190716112319

Price: $65

Abstract

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

Keywords: Adenosine, adenosine receptors, adenosine triphosphate, alzheimer’s disease, cancer, asthma, epilepsy.

« Previous
[1]
Sachdeva S, Gupta M. Adenosine and its receptors as therapeutic targets: An overview. Saudi Pharm J 2013; 21(3): 245-53.
[http://dx.doi.org/10.1016/j.jsps.2012.05.011] [PMID: 23960840]
[2]
Layland J, Carrick D, Lee M, Oldroyd K, Berry C. Adenosine: Physiology, pharmacology, and clinical applications. JACC Cardiovasc Interv 2014; 7(6): 581-91.
[http://dx.doi.org/10.1016/j.jcin.2014.02.009] [PMID: 24835328]
[3]
de Lera Ruiz M, Lim YH, Zheng J. Adenosine A2A receptor as a drug discovery target. J Med Chem 2014; 57(9): 3623-50.
[http://dx.doi.org/10.1021/jm4011669] [PMID: 24164628]
[4]
Olah ME. Identification of A2a adenosine receptor domains involved in selective coupling to Gs. Analysis of chimeric A1/A2a adenosine receptors. J Biol Chem 1997; 272(1): 337-44.
[http://dx.doi.org/10.1074/jbc.272.1.337] [PMID: 8995267]
[5]
Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine receptors: Expression, function and regulation. Int J Mol Sci 2014; 15(2): 2024-52.
[http://dx.doi.org/10.3390/ijms15022024] [PMID: 24477263]
[6]
Piirainen H, Ashok Y, Nanekar RT, Jaakola VP. Structural features of adenosine receptors: From crystal to function. Biochim Biophys Acta 2011; 1808(5): 1233-44.
[http://dx.doi.org/10.1016/j.bbamem.2010.05.021] [PMID: 20595055]
[7]
Chandrasekaran B, Deb PK, Kachler S, Akkinepalli RR, Mailavaram R, Klotz KN. Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido [2, 3-d] pyrimidines and quinazolines. Med Chem Res 2018; 27: 756-67.
[http://dx.doi.org/10.1007/s00044-017-2099-z]
[8]
Shaik K, Deb PK, Mailavaram RP, et al. 7-Amino-2-aryl/hetero-aryl-5-oxo-5,8-dihydro[1,2,4]triazolo[1,5-a]pyridine-6-carbonitriles: Synthesis and adenosine receptor binding studies. Chem Biol Drug Des 2019; 94(2): 1568-73.
[http://dx.doi.org/10.1111/cbdd.13528] [PMID: 30985956]
[9]
Latini S, Pedata F. Adenosine in the central nervous system: Release mechanisms and extracellular concentrations. J Neurochem 2001; 79(3): 463-84.
[http://dx.doi.org/10.1046/j.1471-4159.2001.00607.x] [PMID: 11701750]
[10]
Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 2001; 24: 31-55.
[http://dx.doi.org/10.1146/annurev.neuro.24.1.31] [PMID: 11283304]
[11]
Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K. Pharmacology of adenosine receptors: The state of the art. Physiol Rev 2018; 98(3): 1591-625.
[http://dx.doi.org/10.1152/physrev.00049.2017] [PMID: 29848236]
[12]
Fried NT, Elliott MB, Oshinsky ML. The role of adenosine signaling in headache: A review. Brain Sci 2017; 7(3): 1-20.
[http://dx.doi.org/10.3390/brainsci7030030] [PMID: 28335379]
[13]
Sperlágh B, Vizi ES. The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: pharmacological and clinical aspects. Curr Top Med Chem 2011; 11(8): 1034-46.
[http://dx.doi.org/10.2174/156802611795347564] [PMID: 21401497]
[14]
Dux E, Fastbom J, Ungerstedt U, Rudolphi K, Fredholm BB. Protective effect of adenosine and a novel xanthine derivative propentofylline on the cell damage after bilateral carotid occlusion in the gerbil hippocampus. Brain Res 1990; 516(2): 248-56.
[http://dx.doi.org/10.1016/0006-8993(90)90925-2] [PMID: 2364291]
[15]
Jacobson KA, Trivedi BK, Churchill PC, Williams M. Novel therapeutics acting via purine receptors. Biochem Pharmacol 1991; 41(10): 1399-410.
[http://dx.doi.org/10.1016/0006-2952(91)90555-J] [PMID: 2018549]
[16]
Chen JF, Eltzschig HK, Fredholm BB. Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 2013; 12(4): 265-86.
[http://dx.doi.org/10.1038/nrd3955] [PMID: 23535933]
[17]
Sousa JB, Diniz C. The adenosinergic system as a therapeutic target in the vasculature: New ligands and challenges. Molecules 2017; 22(5): 1-27.
[http://dx.doi.org/10.3390/molecules22050752] [PMID: 28481238]
[18]
Pleli T, Mondorf A, Ferreiros N, et al. Activation of adenylyl cyclase causes stimulation of adenosine receptors. Cell Physiol Biochem 2018; 45(6): 2516-28.
[http://dx.doi.org/10.1159/000488270] [PMID: 29587249] [http://dx.doi.org/10.1038/nrendo.2015.10] [PMID: 25687993]
[19]
Kusakabe Y, Ishihara M, Umeda T, et al. Structural insights into the reaction mechanism of S-adenosyl-L-homocysteine hydrolase. Sci Rep 2015; 5: 16641.
[http://dx.doi.org/10.1038/srep16641] [PMID: 26573329] [http://dx.doi.org/10.1159/000488270] [PMID: 29587249]
[20]
Morandi F, Horenstein AL, Rizzo R, Malavasi F. The role of extracellular adenosine generation in the development of autoimmune diseases. Mediators Inflamm 2018; 20187019398
[http://dx.doi.org/10.1155/2018/7019398] [PMID: 29769837]
[21]
Camici M, Garcia-Gil M, Tozzi MG. The inside story of adenosine. Int J Mol Sci 2018; 19(3): 784.
[http://dx.doi.org/10.3390/ijms19030784] [PMID: 29522447] [http://dx.doi.org/10.3390/ijms15022024] [PMID: 24477263]
[22]
Stumpe T, Schrader J. Phosphorylation potential, adenosine formation, and critical PO2 in stimulated rat cardiomyocytes. Am J Physiol 1997; 273(2 Pt 2): H756-66.
[PMID: 9277493]
[23]
Ferré S, Quiroz C, Woods AS, et al. An update on adenosine A2A-dopamine D2 receptor interactions: implications for the function of G protein-coupled receptors. Curr Pharm Des 2008; 14(15): 1468-74.
[http://dx.doi.org/10.2174/138161208784480108] [PMID: 18537670]
[24]
Cunha RA. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: Different roles, different sources and different receptors. Neurochem Int 2001; 38(2): 107-25.
[http://dx.doi.org/10.1016/S0197-0186(00)00034-6] [PMID: 11137880]
[25]
Dzeja P, Terzic A. Adenylate kinase and AMP signaling networks: Metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 2009; 10(4): 1729-72.
[http://dx.doi.org/10.3390/ijms10041729] [PMID: 19468337]
[26]
Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochim Biophys Acta 2011; 1808(5): 1380-99.
[http://dx.doi.org/10.1016/j.bbamem.2010.12.001] [PMID: 21145878]
[27]
Franco R, Navarro G. Adenosine A2A receptor antagonists in neurodegenerative diseases: Huge potential and huge challenges. Front Psychiatry 2018; 9: 68.
[http://dx.doi.org/10.3389/fpsyt.2018.00068] [PMID: 29593579]
[28]
Lasley RD. Adenosine receptor-mediated cardioprotection-current limitations and future directions. Front Pharmacol 2018; 9: 310.
[http://dx.doi.org/10.3389/fphar.2018.00310] [PMID: 29670529]
[29]
Ponnoth DS, Jamal Mustafa S. Adenosine receptors and vascular inflammation. Biochim Biophys Acta 2011; 1808(5): 1429-34.
[http://dx.doi.org/10.1016/j.bbamem.2010.08.024] [PMID: 20832387]
[30]
Borea PA, Varani K, Vincenzi F, et al. The A3 adenosine receptor: History and perspectives. Pharmacol Rev 2015; 67(1): 74-102.
[http://dx.doi.org/10.1124/pr.113.008540] [PMID: 25387804]
[31]
Boison D. Adenosine dysfunction in epilepsy. Glia 2012; 60(8): 1234-43.
[http://dx.doi.org/10.1002/glia.22285] [PMID: 22700220]
[32]
Boison D, Steinhäuser C. Epilepsy and astrocyte energy metabolism. Glia 2018; 66(6): 1235-43.
[http://dx.doi.org/10.1002/glia.23247] [PMID: 29044647]
[33]
Cellai L, Carvalho K, Faivre E, et al. The adenosinergic signaling: A complex but promising therapeutic target for Alzheimer’s disease. Front Neurosci 2018; 12: 520.
[http://dx.doi.org/10.3389/fnins.2018.00520] [PMID: 30123104]
[34]
Boison D. Adenosine as a neuromodulator in neurological diseases. Curr Opin Pharmacol 2008; 8(1): 2-7.
[http://dx.doi.org/10.1016/j.coph.2007.09.002] [PMID: 17942368]
[35]
Landolt HP, Rétey JV, Adam M. Reduced neurobehavioral impairment from sleep deprivation in older adults: Contribution of adenosinergic mechanisms. Front Neurol 2012; 3: 62.
[http://dx.doi.org/10.3389/fneur.2012.00062] [PMID: 22557989]
[36]
Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 2007; 83(5): 277-92.
[http://dx.doi.org/10.1016/j.pneurobio.2007.05.001] [PMID: 17646043]
[37]
Festugato M. Adenosine: An endogenous mediator in the pathogenesis of psoriasis. An Bras Dermatol 2015; 90(6): 862-7.
[http://dx.doi.org/10.1590/abd1806-4841.20153689] [PMID: 26734868]
[38]
Cacciari B, Spalluto G, Federico S. A2A adenosine receptor antagonists as therapeutic candidates: Are they still an interesting challenge? Mini Rev Med Chem 2018; 18(14): 1168-74.
[http://dx.doi.org/10.2174/1389557518666180423113051] [PMID: 29692248] [http://dx.doi.org/10.1089/caff.2018.0017] [PMID: 30596206]
[39]
López-Cruz L, Salamone JD, Correa M. Caffeine and selective adenosine receptor antagonists as new therapeutic tools for the motivational symptoms of depression. Front Pharmacol 2018; 9: 526.
[http://dx.doi.org/10.3389/fphar.2018.00526] [PMID: 29910727]
[40]
Ferré S, Quiroz C, Woods AS, et al. An update on adenosine A2A-dopamine D2 receptor interactions: Implications for the function of G protein-coupled receptors. Curr Pharm Des 2008; 14(15): 1468-74.
[http://dx.doi.org/10.2174/138161208784480108] [PMID: 18537670]
[41]
Holst SC, Landolt HP. Sleep Homeostasis, Metabolism, and Adenosine. Curr Sleep Med Rep 2015; 1: 27-37.
[http://dx.doi.org/10.1007/s40675-014-0007-3]
[42]
Ballesteros-Yáñez I, Castillo CA, Merighi S, Gessi S. The role of adenosine receptors in psychostimulant addiction. Front Pharmacol 2018; 8: 985.
[http://dx.doi.org/10.3389/fphar.2017.00985] [PMID: 29375384]
[43]
Fredholm BB. Adenosine receptors as drug targets. Exp Cell Res 2010; 316(8): 1284-8.
[http://dx.doi.org/10.1016/j.yexcr.2010.02.004] [PMID: 20153317]
[44]
Klotz KN. Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch Pharmacol 2000; 362(4-5): 382-91.
[http://dx.doi.org/10.1007/s002100000315] [PMID: 11111832]
[45]
Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K. Pharmacology of adenosine receptors: The state of the art. Physiol Rev 2018; 98(3): 1591-625.
[http://dx.doi.org/10.1152/physrev.00049.2017] [PMID: 29848236]
[46]
Bantel C, Childers SR, Eisenach JC. Role of adenosine receptors in spinal G-protein activation after peripheral nerve injury. Anesthesiology 2002; 96(6): 1443-9.
[http://dx.doi.org/10.1097/00000542-200206000-00025] [PMID: 12170058]
[47]
Matasi JJ, Caldwell JP, Hao J, et al. The discovery and synthesis of novel adenosine receptor (A(2A)) antagonists. Bioorg Med Chem Lett 2005; 15(5): 1333-6.
[http://dx.doi.org/10.1016/j.bmcl.2005.01.019] [PMID: 15713381]
[48]
Carlsson J, Yoo L, Gao ZG, Irwin JJ, Shoichet BK, Jacobson KA. Structure-based discovery of A2A adenosine receptor ligands. J Med Chem 2010; 53(9): 3748-55.
[http://dx.doi.org/10.1021/jm100240h] [PMID: 20405927]
[49]
Balakumar C, Kishore DP, Rao KV, et al. Design, microwave-assisted synthesis and in silico docking studies of new 4h-pyrimido[2,1-b]-benzothiazole-2-arylamino-3-cyano-4-ones as possible adenosine a2b receptor antagonists. Indian J Chem 2012; 51B: 1105-13.
[50]
Deb PK, Chandrasekaran B, Mailavaram R, Tekade RK, Jaber AMY. Molecular modeling approaches for the discovery of adenosine A2B receptor antagonists: current status and future perspectives. Drug Discov Today 2019; 24(9): 1854-64.
[http://dx.doi.org/10.1016/j.drudis.2019.05.011] [PMID: 31103731]
[51]
Jacobson KA, Merighi S, Varani K, et al. A3 adenosine receptors as modulators of inflammation: From medicinal chemistry to therapy. Med Res Rev 2018; 38(4): 1031-72.
[http://dx.doi.org/10.1002/med.21456] [PMID: 28682469]
[52]
Zimmermann H. Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 2000; 362(4-5): 299-309.
[http://dx.doi.org/10.1007/s002100000309] [PMID: 11111825]
[53]
McGaraughty S, Cowart M, Jarvis MF, Berman RF. Anticonvulsant and antinociceptive actions of novel adenosine kinase inhibitors. Curr Top Med Chem 2005; 5(1): 43-58.
[http://dx.doi.org/10.2174/1568026053386845] [PMID: 15638777]
[54]
Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001; 53(4): 527-52.
[PMID: 11734617]
[55]
Linden J. Adenosine in tissue protection and tissue regeneration. Mol Pharmacol 2005; 67(5): 1385-7.
[http://dx.doi.org/10.1124/mol.105.011783] [PMID: 15703375]
[56]
Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 2011; 1808(5): 1290-308.
[http://dx.doi.org/10.1016/j.bbamem.2010.12.017] [PMID: 21185259]
[57]
Fernández-Dueñas V, Gómez-Soler M, López-Cano M, et al. Uncovering caffeine’s adenosine A2A receptor inverse agonism in experimental parkinsonism. ACS Chem Biol 2014; 9(11): 2496-501.
[http://dx.doi.org/10.1021/cb5005383] [PMID: 25268872]
[58]
Cieślak M, Komoszyński M, Wojtczak A. Adenosine A(2A) receptors in Parkinson’s disease treatment. Purinergic Signal 2008; 4(4): 305-12.
[http://dx.doi.org/10.1007/s11302-008-9100-8] [PMID: 18438720]
[59]
Fredholm BB. Physiological and pathophysiological roles of adenosine. Sleep Biol Rhythms 2011; 9: 24-8.
[http://dx.doi.org/10.1111/j.1479-8425.2010.00460.x]
[60]
Liang BT, Jacobson KA, Herrmann HC, Kimmel S, Jacoboson KA. Adenosine and ischemic preconditioning. Curr Pharm Des 1999; 5(12): 1029-41.
[PMID: 10607860]
[61]
Müller C, Jacobson KA. Xanthines as Adenosine Receptor Antagonists. In: Handb Exp Pharmaco. 2014; pp. 1-59.
[62]
Gao ZG, Blaustein JB, Gross AS, Melman N, Jacobson KAN. N6-Substituted adenosine derivatives: selectivity, efficacy, and species differences at A3 adenosine receptors. Biochem Pharmacol 2003; 65(10): 1675-84.
[http://dx.doi.org/10.1016/S0006-2952(03)00153-9] [PMID: 12754103]
[63]
Sudo SZ, Alencar AKN, Sudo RT. Targeting of the adenosine receptors as a novel strategy for the treatment of arterial hypertension. J Neurol Neurophysiol 2014; 5: 1-9.
[64]
Rieger JM, Brown ML, Sullivan GW, Linden J, Macdonald TL. Design, synthesis, and evaluation of novel A2A adenosine receptor agonists. J Med Chem 2001; 44(4): 531-9.
[http://dx.doi.org/10.1021/jm0003642] [PMID: 11170643]
[65]
Shimada J, Suzuki F, Nonaka H, Ishii A, Ichikawa S. (E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: Potent and selective adenosine A2 antagonists. J Med Chem 1992; 35(12): 2342-5.
[http://dx.doi.org/10.1021/jm00090a027] [PMID: 1613758]
[66]
Collins LE, Sager TN, Sams AG, et al. The novel adenosine A2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade. Pharmacol Biochem Behav 2012; 100(3): 498-505.
[http://dx.doi.org/10.1016/j.pbb.2011.10.015] [PMID: 22037410]
[67]
Armentero MT, Pinna A, Ferré S, Lanciego JL, Müller CE, Franco R. Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 2011; 132(3): 280-99.
[http://dx.doi.org/10.1016/j.pharmthera.2011.07.004] [PMID: 21810444]
[68]
Stewart M, Steinig AG, Ma C, et al. [3H]OSIP339391, a selective, novel, and high affinity antagonist radioligand for adenosine A2B receptors. Biochem Pharmacol 2004; 68(2): 305-12.
[http://dx.doi.org/10.1016/j.bcp.2004.03.026] [PMID: 15194002]
[69]
Ponnoth DS, Jamal Mustafa S. Adenosine receptors and vascular inflammation. Biochim Biophys Acta 2011; 1808(5): 1429-34.
[http://dx.doi.org/10.1016/j.bbamem.2010.08.024] [PMID: 20832387]
[70]
Baraldi PG, Tabrizi MA, Gessi S, Borea PA. Adenosine receptor antagonists: Translating medicinal chemistry and pharmacology into clinical utility. Chem Rev 2008; 108(1): 238-63.
[http://dx.doi.org/10.1021/cr0682195] [PMID: 18181659]
[71]
Tchilibon S, Joshi BV, Kim SK, Duong HT, Gao ZG, Jacobson KA. (N)-methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists. J Med Chem 2005; 48(6): 1745-58.
[http://dx.doi.org/10.1021/jm049580r] [PMID: 15771421]
[72]
Moro S, Gao ZG, Jacobson KA, Spalluto G. Progress in the pursuit of therapeutic adenosine receptor antagonists. Med Res Rev 2006; 26(2): 131-59.
[http://dx.doi.org/10.1002/med.20048] [PMID: 16380972]
[73]
Müller CE, Diekmann M, Thorand M, Ozola V. [(3)H]8-Ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]-purin-5-one ([(3)H]PSB-11), a novel high-affinity antagonist radioligand for human A(3) adenosine receptors. Bioorg Med Chem Lett 2002; 12(3): 501-3.
[http://dx.doi.org/10.1016/S0960-894X(01)00785-5] [PMID: 11814828]
[74]
Jacobson KA, Merighi S, Varani K, et al. A3 adenosine receptors as modulators of inflammation: from medicinal chemistry to therapy. Med Res Rev 2018; 38(4): 1031-72.
[http://dx.doi.org/10.1002/med.21456] [PMID: 28682469]
[75]
Moro S, Bacilieri M, Cacciari B, Spalluto G. Autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as new strategy for the prediction of the activity of human A(3) adenosine receptor antagonists. J Med Chem 2005; 48(18): 5698-704.
[http://dx.doi.org/10.1021/jm0502440] [PMID: 16134938]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy