Abstract
Adenosine receptors (ARs) are a class of G-protein coupled receptors (GPCRs) that are activated by the endogenous substance adenosine. ARs are classified into 4 subtype receptors, namely, the A1, A2A, A2B and A3 receptors. The wide distribution and expression of the ARs in various body tissues as well as the roles they have in controlling different functions in the body make them potential drug targets for the treatment of various pathological conditions, such as cardiac diseases, cancer, Parkinson’s disease, inflammation and glaucoma. Therefore, in the past decades, there have been extensive investigations of ARs with a high number of agonists and antagonists identified that can interact with these receptors. This review shall discuss the A2A receptor (A2AAR) subtype of the ARs. The structure, properties and the recent advances in the therapeutic potential of the receptor are discussed with an overview of the recent advances in the methods of studying the receptor. Also, molecular modeling approaches utilized in the design of A2AAR ligands are highlighted with various recent examples.
Keywords: Adenosine A2A receptor, molecular modeling, myocardial perfusion imaging, Parkinson’s disease, depression, cancer immunotherapy.
[http://dx.doi.org/10.1016/j.bbamem.2010.12.017] [PMID: 21185259]
[http://dx.doi.org/10.1021/jm300206u] [PMID: 22432713]
[http://dx.doi.org/10.2174/1389200215666140217110716] [PMID: 24533801]
[http://dx.doi.org/10.3390/molecules22061010] [PMID: 28629145]
[http://dx.doi.org/10.1021/ci500639g] [PMID: 25625646]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00204] [PMID: 29792714]
[http://dx.doi.org/10.3390/molecules23081846] [PMID: 30044380]
[http://dx.doi.org/10.3109/10799893.2012.660532] [PMID: 22384789]
[http://dx.doi.org/10.1142/S0219633610006146]
[http://dx.doi.org/10.1117/12.2281326]
[http://dx.doi.org/10.2174/0929867325666180313110254] [PMID: 29532748]
[http://dx.doi.org/10.3109/14017431.2016.1163415] [PMID: 26956081]
[http://dx.doi.org/10.1007/s12350-014-0050-y] [PMID: 25677160]
[http://dx.doi.org/10.1080/17460441.2018.1534825] [PMID: 30336706]
[http://dx.doi.org/10.2174/1389557518666180423113051] [PMID: 29692248]
[http://dx.doi.org/10.1002/med.21344] [PMID: 25821194]
[http://dx.doi.org/10.3389/fpsyt.2018.00068] [PMID: 29593579]
[http://dx.doi.org/10.1124/mol.112.084509]
[http://dx.doi.org/10.1016/j.str.2017.12.013]
[http://dx.doi.org/10.1124/mol.114.097360]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00653] [PMID: 27312113]
[http://dx.doi.org/10.1016/j.cell.2017.12.004]
[http://dx.doi.org/10.1038/s41598-017-18570-w] [PMID: 29311713]
[http://dx.doi.org/10.1038/s41467-017-00630-4] [PMID: 28912485]
[http://dx.doi.org/10.1021/jm100240h] [PMID: 20405927]
[http://dx.doi.org/10.1124/mol.115.102657]
[http://dx.doi.org/10.1016/j.str.2011.06.014] [PMID: 21885291]
[http://dx.doi.org/10.1126/science.1164772] [PMID: 18832607]
[http://dx.doi.org/10.1126/science.1202793] [PMID: 21393508]
[http://dx.doi.org/10.2174/1568026033392200] [PMID: 12570759]
[http://dx.doi.org/10.2174/138161208784746842] [PMID: 18673194]
[http://dx.doi.org/10.1021/jm4011669] [PMID: 24164628]
[http://dx.doi.org/10.1016/j.cardiores.2004.05.015] [PMID: 15306230]
[http://dx.doi.org/10.1016/j.pneurobio.2007.07.005] [PMID: 17804147]
[http://dx.doi.org/10.1038/nri.2016.4] [PMID: 26922909]
[http://dx.doi.org/10.1111/cbdd.13528]
[http://dx.doi.org/10.1016/j.bmc.2012.11.021] [PMID: 23245803]
[http://dx.doi.org/10.1038/nature10136] [PMID: 21593763]
[http://dx.doi.org/10.1021/jm201461q] [PMID: 22104008]
[http://dx.doi.org/10.1021/jm201229j] [PMID: 22142423]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00215] [PMID: 25780876]
[http://dx.doi.org/10.1021/ml200189u] [PMID: 24900277]
[http://dx.doi.org/10.1021/ml5002486] [PMID: 25221664]
[http://dx.doi.org/10.1016/S0968-0896(03)00123-8] [PMID: 12713828]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00552] [PMID: 27227326]
[http://dx.doi.org/10.1021/cn2000537] [PMID: 22860156]
[http://dx.doi.org/10.1016/j.bmc.2016.04.048] [PMID: 27161878]
[http://dx.doi.org/10.1021/jm201640m] [PMID: 22239465]
[http://dx.doi.org/10.1016/j.bmcl.2009.12.028] [PMID: 20034788]
[http://dx.doi.org/10.1016/j.bmcl.2010.04.058] [PMID: 20483600]
[http://dx.doi.org/10.1016/j.bmcl.2015.01.062] [PMID: 25701253]
[http://dx.doi.org/10.1016/j.ejmech.2017.12.007] [PMID: 29268131]
[http://dx.doi.org/10.1021/jm501254d] [PMID: 25490054]
[http://dx.doi.org/10.1016/j.bioorg.2017.08.013] [PMID: 28881253]
[http://dx.doi.org/10.1016/j.bmcl.2016.10.086] [PMID: 27836398]
[http://dx.doi.org/10.1016/j.bioorg.2018.01.004] [PMID: 29353730]
[http://dx.doi.org/10.1016/j.tips.2014.06.003] [PMID: 25042457]
[http://dx.doi.org/10.1021/cb5005383] [PMID: 25268872]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01068] [PMID: 27933962]
[http://dx.doi.org/10.1016/j.bmc.2018.05.048] [PMID: 29880250]
[http://dx.doi.org/10.1016/j.neuron.2017.03.016] [PMID: 28472649]
[http://dx.doi.org/10.1517/17460441.2015.971006] [PMID: 25311639]
[http://dx.doi.org/10.1124/mol.114.095737] [PMID: 25473121]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00142] [PMID: 27124340]
[http://dx.doi.org/10.1016/B978-0-12-814421-3.00019-1]
[http://dx.doi.org/10.2174/1381612825666190304122624] [PMID: 30834826]
[http://dx.doi.org/10.2174/1381612825666190306162006] [PMID: 30848185]
[http://dx.doi.org/10.2174/1381612825666190304123545] [PMID: 30836910]
[http://dx.doi.org/10.2174/1381612825999190515120510] [PMID: 31232230]
[http://dx.doi.org/10.1016/j.drudis.2019.05.011] [PMID: 31103731]
[http://dx.doi.org/10.1007/s00044-017-2099-z]
[http://dx.doi.org/10.1371/journal.pone.0204378] [PMID: 30605479]
[http://dx.doi.org/10.1016/j.bmcl.2010.11.094] [PMID: 21163647]
[http://dx.doi.org/10.1111/cbdd.13155] [PMID: 29194979]
[http://dx.doi.org/10.2174/1381612825666190304123414] [PMID: 30834825]
[http://dx.doi.org/10.4155/fmc.11.63] [PMID: 21707404]
[http://dx.doi.org/10.1016/j.cbi.2016.05.023] [PMID: 27216633]
[http://dx.doi.org/10.1016/j.biosystems.2013.04.003] [PMID: 23665268]
[http://dx.doi.org/10.1007/s00044-016-1575-1]
[http://dx.doi.org/10.1038/srep36595] [PMID: 27812030]
[http://dx.doi.org/10.1080/1062936X.2015.1136840] [PMID: 26873265]
[http://dx.doi.org/10.1021/ci300615u] [PMID: 23705857]
[http://dx.doi.org/10.1039/C3MD00338H]
[http://dx.doi.org/10.1021/ci5002857] [PMID: 25046649]
[http://dx.doi.org/10.1007/s10822-016-9918-z] [PMID: 27334985]
[http://dx.doi.org/10.1021/jm901647p] [PMID: 20095623]
[http://dx.doi.org/10.1080/1062936X.2015.1049666] [PMID: 26055215]
[http://dx.doi.org/10.1016/j.bmcl.2015.05.036] [PMID: 26048804]
[PMID: 26604800]
[http://dx.doi.org/10.1021/ci300610w] [PMID: 23514445]
[http://dx.doi.org/10.1021/ci400532b] [PMID: 24359090]
[http://dx.doi.org/10.1517/13543784.14.7.797] [PMID: 16022569]
[http://dx.doi.org/10.1182/blood-2007-01-065870] [PMID: 17525287]
[http://dx.doi.org/10.1038/ni.3049] [PMID: 25521684]
[http://dx.doi.org/10.1016/j.pupt.2017.04.009] [PMID: 28499635]
[PMID: 24511476]
[http://dx.doi.org/10.1152/ajplung.00422.2005] [PMID: 16339780]
[http://dx.doi.org/10.1016/j.ejmech.2014.01.045] [PMID: 24556147]
[http://dx.doi.org/10.1016/j.matbio.2016.01.013] [PMID: 26844756]
[http://dx.doi.org/10.1038/s41467-017-02425-z] [PMID: 29295997]
[http://dx.doi.org/10.1124/jpet.117.244319] [PMID: 29212832]
[http://dx.doi.org/10.1007/s10753-015-0184-3] [PMID: 25991438]
[PMID: 24483158]
[http://dx.doi.org/10.1007/s11302-016-9498-3] [PMID: 26847815]
[http://dx.doi.org/10.1111/bph.13615] [PMID: 27595240]
[http://dx.doi.org/10.1007/s12350-011-9474-9] [PMID: 22130964]
[http://dx.doi.org/10.1517/14728214.2011.644786]
[http://dx.doi.org/10.2967/jnmt.109.065581]
[http://dx.doi.org/10.1007/s12350-010-9211-9] [PMID: 20221857]
[http://dx.doi.org/10.1097/CRD.0b013e3182613db6] [PMID: 22643345]
[http://dx.doi.org/10.1007/s11302-008-9100-8] [PMID: 18438720]
[http://dx.doi.org/10.1001/jama.2014.3654] [PMID: 24756517]
[http://dx.doi.org/10.1002/mds.25945] [PMID: 24976103]
[http://dx.doi.org/10.1093/brain/awh128] [PMID: 15033896]
[http://dx.doi.org/10.1212/01.WNL.0000095218.26363.7B] [PMID: 14663016]
[http://dx.doi.org/10.1212/01.WNL.0000073136.00548.D4] [PMID: 12913186]
[http://dx.doi.org/10.1016/j.jns.2006.05.019] [PMID: 16765381]
[http://dx.doi.org/10.1080/14656566.2018.1518433] [PMID: 30281377]
[http://dx.doi.org/10.1212/01.WNL.0000081227.84197.0B] [PMID: 12913187]
[http://dx.doi.org/10.1021/mp200489d] [PMID: 22292533]
[http://dx.doi.org/10.1016/j.pharmthera.2011.07.004] [PMID: 21810444]
[http://dx.doi.org/10.1016/S0968-0896(02)00648-X] [PMID: 12628657]
[http://dx.doi.org/10.1016/j.neuint.2009.09.001] [PMID: 19782116]
[http://dx.doi.org/10.1007/s00401-015-1390-7] [PMID: 25628035]
[http://dx.doi.org/10.1046/j.1468-1331.2002.00421.x] [PMID: 12099922]
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.08.010] [PMID: 28941407]
[http://dx.doi.org/10.1038/mp.2014.151] [PMID: 25450226]
[http://dx.doi.org/10.1016/j.expneurol.2006.08.008] [PMID: 17007839]
[http://dx.doi.org/10.3389/fnmol.2018.00235] [PMID: 30050407]
[http://dx.doi.org/10.1021/jm9911480] [PMID: 10669571]
[http://dx.doi.org/10.1016/j.pbb.2009.11.011] [PMID: 19958787]
[http://dx.doi.org/10.1016/j.nbd.2018.05.024] [PMID: 29859867]
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.027] [PMID: 24780254]
[http://dx.doi.org/10.1038/nrdp.2016.65] [PMID: 27629598]
[http://dx.doi.org/10.1001/jama.2017.5706] [PMID: 28535241]
[http://dx.doi.org/10.1037/0735-7044.117.1.123] [PMID: 12619915]
[http://dx.doi.org/10.1177/0271678X16650696] [PMID: 27217381]
[http://dx.doi.org/10.1016/j.psychres.2016.10.007] [PMID: 27788463]
[http://dx.doi.org/10.3389/fpsyt.2014.00067] [PMID: 24982640]
[http://dx.doi.org/10.1016/j.bbr.2016.12.020] [PMID: 28007538]
[http://dx.doi.org/10.1016/j.biopsych.2013.05.003] [PMID: 23820821]
[http://dx.doi.org/10.1038/mp.2016.173] [PMID: 27725661]
[http://dx.doi.org/10.1212/01.WNL.0000095220.87550.F6] [PMID: 14663017]
[http://dx.doi.org/10.1177/0269881115609072] [PMID: 26464458]
[PMID: 30267268]
[http://dx.doi.org/10.1002/brb3.952] [PMID: 29761007]
[http://dx.doi.org/10.1038/s41563-018-0091-8] [PMID: 29795216]
[http://dx.doi.org/10.1126/science.aar4060] [PMID: 29567705]
[http://dx.doi.org/10.3389/fimmu.2017.01933] [PMID: 29410662]
[http://dx.doi.org/10.3892/ol.2018.9219] [PMID: 30214551]
[http://dx.doi.org/10.2217/imt-2017-0168] [PMID: 30326786]
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
[http://dx.doi.org/10.1038/414916a] [PMID: 11780065]
[http://dx.doi.org/10.1007/s00262-011-1155-7] [PMID: 22116345]
[http://dx.doi.org/10.1016/j.neo.2017.02.004] [PMID: 28582704]
[http://dx.doi.org/10.1186/s12943-017-0665-0] [PMID: 28592285]
[http://dx.doi.org/10.1111/bph.13763] [PMID: 28252203]
[http://dx.doi.org/10.4161/cbt.25643] [PMID: 23917542]
[http://dx.doi.org/10.3389/fphar.2017.00888] [PMID: 29249971]