Simulation and comparative analysis of binding modes of nucleoside and non-nucleoside agonists at the A2B adenosine receptor
© Dal Ben et al.; licensee Springer. 2013
Received: 31 October 2013
Accepted: 11 December 2013
Published: 20 December 2013
A2B receptor agonists are studied as possible therapeutic tools for a variety of pathological conditions. Unfortunately, medicinal chemistry efforts have led to the development of a limited number of potent agonists of this receptor, in most cases with a low or no selectivity versus the other adenosine receptor subtypes. Among the developed molecules, two structural families of compounds have been identified based on nucleoside and non-nucleoside (pyridine) scaffolds. The aim of this work is to analyse the binding mode of these molecules at 3D models of the human A2B receptor to identify possible common interaction features and the key receptor residues involved in ligand interaction.
The A2B receptor models are built by using two recently published crystal structures of the human A2A receptor in complex with two different agonists. The developed models are used as targets for molecular docking studies of nucleoside and non-nucleoside agonists. The generated docking conformations are subjected to energy minimization and rescoring by using three different scoring functions. Further analysis of top-score conformations are performed with a tool evaluating the interaction energy between the ligand and the binding site residues.
Results suggest a set of common interaction points between the two structural families of agonists and the receptor binding site, as evidenced by the superimposition of docking conformations and by analysis of interaction energy with the receptor residues.
The obtained results show that there is a conserved pattern of interaction between the A2B receptor and its agonists. These information and can provide useful data to support the design and the development of A2B receptor agonists belonging to nucleoside or non-nucleoside structural families.
KeywordsPurinergic receptors Adenosine receptors Adenosine receptor agonists Nucleosides Purine derivatives Pyridine derivatives Molecular modelling Homology modelling Molecular docking
Among ARs, the A2BAR has been usually defined “low-affinity AR” due to its lower affinity for Ado and for other agonists respect to the other AR subtypes (Feoktistov and Biaggioni 1997; Beukers et al. 2000). Its stimulation leads to activation of phospholipase C and adenylyl cyclase through the coupling to the Gq and Gs proteins, respectively. The A2BAR is widely expressed in the human body and regulates several biological events at cardiovascular, muscular, and central nervous systems, and also in cell growth and during inflammation (Feoktistov and Biaggioni 1997). Hence, this receptor is of therapeutic interest for its targeting in several conditions (Baraldi et al. 2009). In particular, the agonists of this receptor have been evaluated for their cardioprotective effect, due to their reduced bradycardic and hypotensive side effects respect to Ado (Kuno et al. 2007; Philipp et al. 2006; Gao and Jacobson 2007; Eckle et al. 2007), for the treatment of coronary artery disease (Hinschen et al. 2003; Ansari et al. 2007; Kemp and Cocks 1999), and to promote angiogenesis (Feoktistov et al. 2003; Feoktistov et al. 2004). Further applications of A2BAR agonists have been explored on the basis of the anti-inflammatory effect following the activation of this receptor, leading to the suggestion of the use of these molecules in septic shock (Kreckler et al. 2006). Even the use of A2BAR agonists for the treatment of renal diseases, hypertension, cystic fibrosis, diabetes, and pulmonary diseases associated with hyperplasia has been considered (Volpini et al. 2003; Dubey et al. 2005).
Nucleoside A 2B AR agonists analysed in this work (see Additional file 1 for structural details)
A2BAR EC50, nM
Non-nucleoside A 2B AR agonists analysed in this work (see Additional file 1 for structural details)
A2BAR EC50, nM
The aim of this work is to analyse the binding mode of both nucleoside and non-nucleoside A2BAR agonists at 3D models of this AR subtype. The compounds presented in Tables 1 and 2 have been considered for this analysis (see Additional file 1 for structural details). As a preliminary step, the study starts from the rebuilding of homology models of the human A2BAR by using as templates the crystal structures of the human A2AAR that is the member of AR family presenting also the highest sequence conservation with the A2BAR. The binding mode of ligands is then simulated by molecular docking tools, followed by energy minimization and post-docking analysis. In this study, it is not possible to depict any correlation between binding scores or interaction energies and activity data, as the potencies of the compounds have been measured as EC50 with functional studies and not as Ki affinity with radioligand binding assays. Furthermore, the study provides an interpretation of the interaction features for both series of ligands at the A2BAR but do not consider the interaction with the other AR subtypes. Hence, the results of this study may provide useful data for the design of A2BAR agonists but not for the improvement of selectivity versus the other ARs.
All molecular modelling studies were performed on a Core i7 CPU (PIV 2.20 GHZ) PC workstation. Homology modelling, energy minimization, and docking studies were carried out using Molecular Operating Environment (MOE, version 2010.10) suite (Molecular Operating Environment). All ligand structures were optimized using RHF/AM1 semiempirical calculations and the software package MOPAC (Stewart 1990) implemented in MOE was used for these calculations.
Homology modelling of the human A2BAR
Homology models of the human A2BAR were built using the recently solved X-ray structures of the human A2AAR in complex with Ado and UK-432097 as templates, both structures being retrieved from Protein Data Bank (pdb code: 2YDO; 3.0-Å resolution (Lebon et al. 2011) and pdb code: 3QAK; 2.7-Å resolution (Xu et al. 2011), respectively). A multiple alignment of the AR primary sequences was built within MOE as a preliminary step. For all A2BAR models, the boundaries identified from the used X-ray crystal structure of A2AAR were then applied for the corresponding sequences of the transmembrane (TM) helices of the A2BAR. The missing loop domains were built by the loop search method implemented in MOE. Once the heavy atoms were modelled, all hydrogen atoms were added, and the protein coordinates were then minimized with MOE using the AMBER99 force field (Cornell et al. 1995) until the Root Mean Square (RMS) gradient of the potential energy was less than 0.05 kJ mol-1 Å-1. Reliability and quality of these models were checked using the Protein Geometry Monitor application within MOE, which provides a variety of stereochemical measurements for inspection of the structural quality in a given protein, like backbone bond lengths, angles and dihedrals, Ramachandran φ-ψ dihedral plots, and quality of side chain rotamer and non-bonded contact.
Molecular docking analysis
All compound structures were docked into the binding site of the two A2BAR models using the MOE Dock tool. This method is divided into a number of stages: Conformational Analysis of ligands. The algorithm generated conformations from a single 3D conformation by conducting a systematic search. In this way, all combinations of angles were created for each ligand. Placement. A collection of poses was generated from the pool of ligand conformations using Triangle Matcher placement method. Poses were generated by superposition of ligand atom triplets and triplet points in the receptor binding site. The receptor site points are alpha sphere centres which represent locations of tight packing. At each iteration a random conformation was selected, a random triplet of ligand atoms and a random triplet of alpha sphere centres were used to determine the pose. Scoring. Poses generated by the placement methodology were scored using two available methods implemented in MOE, the London dG scoring function which estimates the free energy of binding of the ligand from a given pose, and Affinity dG scoring which estimates the enthalpic contribution to the free energy of binding. The top 30 poses for each ligand were output in a MOE database.
Post docking analysis
The five top-score docking poses of each compound were then subjected to AMBER99 force field energy minimization until the RMS gradient of the potential energy was less than 0.05 kJ mol-1 Å-1. Receptor residues within 6 Å distance from the ligand were left free to move, while the remaining receptor coordinates were kept fixed. AMBER99 partial charges of receptor and MOPAC output partial charges of ligands were utilized. Once the compound-binding site energy minimization was completed, receptor coordinates were fixed and a second energy minimization stage was performed leaving free to move only compound atoms. MMFF94 force field (Halgren 1996a, b, c, d;Halgren and Nachbar 1996; Halgren 1999a, b) was applied. For each compound, the minimized docking poses were then rescored using London dG and Affinity dG scoring functions and the dock-pK i predictor. The latter tool allows the estimation of the pKi for each ligand using the “scoring.svl” script retrievable at the SVL exchange service (Chemical Computing Group, Inc. SVL exchange: http://svl.chemcomp.com). The algorithm is based on an empirical scoring function consisting of a directional hydrogen-bonding term, a directional hydrophobic interaction term, and an entropic term (ligand rotatable bonds immobilized in binding). For each compound and at each A2BAR model, the top-score docking poses according to at least two out of three scoring functions were selected for final ligand-target interaction analysis.
The interactions between the ligands and the receptors binding site were analysed by using the IF-E 6.0 tool (Shadnia et al. 2009) retrievable at the SVL exchange service. The program calculates and displays the atomic and residue interaction forces as 3D vectors. It also calculates the per-residue interaction energies, where negative and positive energy values (expressed as kcal mol-1) are associated to favourable and unfavourable interactions, respectively. A shell of residues contained within a 10 Å distance from ligand were considered for this analysis.
Results and discussion
The A2BAR structures were then used as target for the docking analysis of synthesised derivatives. All ligand structures were optimized using RHF/AM1 semi-empirical calculations and the software package MOPAC implemented in MOE was utilized for these calculations (Stewart 1990). The compounds were then docked into the binding site of the A2BAR models by using the MOE Dock tool. Top-score docking poses of each compound were subjected to energy minimization; in this phase the binding site residues within 6 Å proximity were left free to move and to adapt their conformation to the ligand moiety. Once this step was completed, a second minimization phase was performed keeping fixed the receptor coordinates. The obtained ligand-target complexes were then rescored using three available methods implemented in MOE: the London dG scoring function that estimates the free energy of binding of the ligand from a given pose; the Affinity dG scoring tool that estimates the enthalpic contribution to the free energy of binding; the dock-pK i predictor that uses the MOE scoring.svl script to estimate for each ligand a pKi value, which is described by the H-bonds, transition metal interactions, and hydrophobic interactions energy. For each compound, the top-score docking pose at each A2BAR model, according to at least two out of three scoring functions, was selected for final ligand-target interaction analysis.
The binding sites of the two developed A2BAR models are very similar considering both receptor residues orientation and pocket volumes. Slight differences are still observable, due to diverse arrangements of some residues detectable even at the two A2AAR crystal structures templates. For example, a glutamate residue (Glu169 in the A2AAR) located within EL2 segment makes a clear H-bond interaction with the N6-amino group of Ado in the 2YDO crystal structure, while the same residue is oriented in opposite direction when observed within the 3QAK X-ray. This residue presents different orientation even considering four previously reported crystal structures of the A2AAR in complex with ZM241385 antagonist (Jaakola et al. 2008; Dore et al. 2011; Hino et al. 2012; Liu et al. 2012). Furthermore, a recent report on mutagenesis studies at the A2AAR shows that the mutation of this residue does not significantly modify the potency of nucleoside and non-nucleoside agonists at this AR subtype (Lane et al. 2012). These data suggest that the interaction with this residue is important but maybe not critical for the ligand binding to the receptor. Analogously to what observed at the 2YDO and 3QAK crystal structures, comparable arrangements are respectively observed for the corresponding residue (Glu174) at the two A2BAR models. In the second case, this glutamate points towards the side chain of Lys269 (EL3) making a strong polar interaction with this amino acid. In any case, most of differences of binding site residue arrangements are observed at EL domains in peripheral regions of binding site and hence have a marginal impact on the binding site size and chemical-physical properties. As consequence, it is not a surprise that the docking analysis of the synthesised compounds at the two receptor models leads to analogue results.
Considering the non-nucleoside pyridine derivatives, the lowest score and most populated family of docking conformations shows the pyridine ring located in rough correspondence to the adenine scaffold of nucleoside agonists and forming a π-stacking interaction with Phe173 (EL2, Figure 3C-D). Considering the positioning of the different substituents within the binding cavity, the orientation of the pyridine agonists results somehow comparable to the one obtained and schematically described by Sherbiny and colleagues (Sherbiny et al. 2009) but significantly different respect to the ones obtained in more recent docking studies at the same AR subtype (Thimm et al. 2013) and at the A2AAR (Lane et al. 2012). In detail, the interaction of the scaffold with the A2BAR binding site is given as H-bonding between the N1 atom and the 6-amino group of pyridines and the amine and carbonyl groups of Asn2546.55 amide function, respectively. This double polar interaction is clearly present only for some derivatives, due to the nature of the 4-substituent that slightly modifies in some cases the orientation of the scaffold. Analogously to the nucleoside agonists, the amino group at the 6-position of pyridines gives a H-bond interaction with Glu174 in the case of the 2YDO-based A2BAR model, while in the case of the 3QAK-based model the side chain of the same residue in some cases is not close enough to the ligand amino group and hence not able to provide a clear H-bonding. The thiomethylimidazole (7–11) and thioacetamide (12) groups in 2-position are inserted between TM3, TM5, and TM6 residues. In the case of compounds 7–11, the H-bond donor function of imidazole is oriented towards the oxygen atom of Thr893.36, while the acceptor feature points towards the polar hydrogen of His2516.52. In the case of compound 12, analogue interactions are given by the amine and carbonyl functions of thioacetamide group, respectively. The 3-cyano group is inserted in a sub-cavity between Val853.32, Leu863.33, Thr893.36, Ser2797.42, and His2807.43. No clear interaction with binding site is given by this group, even though the presence of some space between this function and the polar groups of Ser2797.42 and His2807.43 could allow the presence of a water molecule providing a sort of “bridge-interaction” between ligand and binding site residues, as observed, for example, in the case of a crystal structure of A2AAR in complex with ZM241385 (Jaakola et al. 2008). The substituted aromatic group at the 4-position is located in a sub-cavity given by TM1, TM2, TM3, and TM7 residues, in close proximity to Tyr101.35, Ala642.61, Ile672.64, Ser682.65, and Ile2767.39. Further residues in proximity of this group are Val853.32 and Phe173. The interaction is mainly hydrophobic, even if polar interaction could be given by the presence of a hydroxyl function on the aromatic substituent (i.e. compounds 8 and 10). Finally, the 5-cyano group points towards the extracellular environment and is located in proximity to the couple of residues Glu174-Lys269.
In conclusion, this study was aimed at simulating the binding modes of nucleoside and non-nucleoside agonists at two A2BAR homology models developed starting from the X-ray structures of the A2AAR in complex with Ado and UK-432097 as templates (pdb code: 2YDO and 3QAK, respectively). The docking conformations of nucleoside derivatives were quite expected, while the non-nucleoside derivatives demonstrated to bind to these receptor models in a different way respect to previously reported studies at AR models. The generated and minimized docking conformations were compared by superimposition and by analysis of the interaction with the binding site residues located in ligand proximity. Results showed that, beside the evident structural differences among the two ligand families, the nucleoside and non-nucleoside derivatives bind to the A2BAR through a series of conserved interaction points, suggesting a sort of interaction pattern. The findings of this analysis are in agreement with the results of the evaluation of the role of binding site residues for the ligand-target interaction and the conclusions of these studies are in good agreement with mutagenesis and molecular modelling studies reported in the last years. Taken together, these data could be helpful for the design of A2BAR agonists belonging to nucleoside or non-nucleoside structural families.
DDB, MB, and CL are Assistant Professors of Medicinal Chemistry with interest in molecular modelling and compound synthesis. AT is post-doctoral researcher working in compound synthesis, while RV is Full Professor of Medicinal Chemistry. All authors work at the School of Pharmacy of the University of Camerino, Italy.
G Protein-coupled receptor
Chinese hamster ovary
Molecular operating environment
protein data bank
Root mean square
This work was supported by Fondo di Ricerca di Ateneo (University of Camerino) and by a grant of the Italian Ministry for University and Research (PRIN2010-11 n° 20103W4779_003).
- Ansari HR, Nadeem A, Talukder MA, Sakhalkar S, Mustafa SJ: Evidence for the involvement of nitric oxide in A 2B receptor-mediated vasorelaxation of mouse aorta. Am J Physiol Heart Circ Physiol 2007, 292: H719-H725.View ArticlePubMedGoogle Scholar
- Ballesteros JA, Weinstein H: Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 1995, 25: 366–428.View ArticleGoogle Scholar
- Baraldi PG, Preti D, Tabrizi MA, Fruttarolo F, Romagnoli R, Carrion MD, Cara LC, Moorman AR, Varani K, Borea PA: Synthesis and biological evaluation of novel 1-deoxy-1-[6-[((hetero)arylcarbonyl)hydrazino]- 9 H -purin-9-yl]- N -ethyl- b -D-ribofuranuronamide derivatives as useful templates for the development of A 2B adenosine receptor agonists. J Med Chem 2007, 50: 374–380. 10.1021/jm061170aView ArticlePubMedGoogle Scholar
- Baraldi PG, Preti D, Tabrizi MA, Fruttarolo F, Saponaro G, Baraldi S, Romagnoli R, Moorman AR, Gessi S, Varani K, Borea PA: N 6 -[(hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5′- N -ethylcarboxamido-adenosines: the first example of adenosine-related structures with potent agonist activity at the human A 2B adenosine receptor. Bioorg Med Chem 2007, 15: 2514–2527. 10.1016/j.bmc.2007.01.055View ArticlePubMedGoogle Scholar
- Baraldi PG, Tabrizi MA, Fruttarolo F, Romagnoli R, Preti D: Recent improvements in the development of A 2B adenosine receptor agonists. Purinergic Signal 2009, 5: 3–19. 10.1007/s11302-009-9140-8PubMed CentralView ArticlePubMedGoogle Scholar
- Beukers MW, den Dulk H, van Tilburg EW, Brouwer J, IJzerman AP: Why are A 2B receptors low-affinity adenosine receptors? Mutation of Asn273 to Tyr increases affinity of human A 2B receptor for 2-(1-Hexynyl)adenosine. Mol Pharmacol 2000, 58: 1349–1356.PubMedGoogle Scholar
- Beukers MW, Chang LC, von Frijtag Drabbe Kunzel JK, Mulder-Krieger T, Spanjersberg RF, Brussee J, IJzerman AP: New, non-adenosine, high-potency agonists for the human adenosine A 2B receptor with an improved selectivity profile compared to the reference agonist N-ethylcarboxamidoadenosine. J Med Chem 2004, 47: 3707–3709. 10.1021/jm049947sView ArticlePubMedGoogle Scholar
- Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA: A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 1995, 117: 5179–5197. 10.1021/ja00124a002View ArticleGoogle Scholar
- Costanzi S, Ivanov AA, Tikhonova IG, Jacobson KA: Structure and function of g protein-coupled receptors studied using sequence analysis, molecular modelling and receptor engineering: adenosine receptors. Front Drug Des Discov 2007, 3: 63–79.Google Scholar
- Cristalli G, Volpini R: Adenosine receptors: chemistry and pharmacology. Curr Top Med Chem 2003, 3: 355–469. 10.2174/1568026033392165View ArticleGoogle Scholar
- Dal Ben D, Buccioni M, Lambertucci C, Marucci G, Thomas A, Volpini R, Cristalli G: Molecular modelling study on potent and selective adenosine A 3 receptor agonists. Bioorg Med Chem 2010, 18: 7923–7930. 10.1016/j.bmc.2010.09.038View ArticlePubMedGoogle Scholar
- Dal Ben D, Lambertucci C, Marucci G, Volpini R, Cristalli G: Adenosine receptor modelling: what does the A 2A crystal structure tell us? Curr Top Med Chem 2010, 10: 993–1018. 10.2174/156802610791293145View ArticlePubMedGoogle Scholar
- Dal Ben D, Buccioni M, Lambertucci C, Kachler S, Falgner N, Marucci G, Thomas A, Cristalli G, Volpini R, Klotz K-N: Different efficacy of adenosine and NECA derivatives at the human A 3 adenosine receptor: insight into the receptor activation switch. Biochem Pharmacol 2013. doi: 10.1016/j.bcp.2013.10.011Google Scholar
- Dore AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH: Structure of the adenosine A 2A receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 2011, 19: 1283–1293. 10.1016/j.str.2011.06.014PubMed CentralView ArticlePubMedGoogle Scholar
- Dubey RK, Gillespie DG, Mi Z, Jackson EK: Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A 2B receptors. Hypertension 2005, 46: 628–634. 10.1161/01.HYP.0000178464.63393.88View ArticlePubMedGoogle Scholar
- Eckle T, Krahn T, Grenz A, Kohler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K, Eltzschig HK: Cardioprotection by ecto-5′-nucleotidase (CD73) and A 2B adenosine receptors. Circulation 2007, 115: 1581–1590. 10.1161/CIRCULATIONAHA.106.669697View ArticlePubMedGoogle Scholar
- Feoktistov I, Biaggioni I: Adenosine A 2B receptors. Pharmacol Rev 1997, 49: 381–402.PubMedGoogle Scholar
- Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I: Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A 2B and A 3 adenosine receptors. Circ Res 2003, 92: 485–492. 10.1161/01.RES.0000061572.10929.2DView ArticlePubMedGoogle Scholar
- Feoktistov I, Ryzhov S, Zhong H, Goldstein AE, Matafonov A, Zeng D, Biaggioni I: Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A 2B angiogenic phenotype. Hypertension 2004, 44: 649–654. 10.1161/01.HYP.0000144800.21037.a5View ArticlePubMedGoogle Scholar
- Fredholm BB, IJzerman AP, Jacobson KA, Klotz K-N, Linden J: International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001, 53: 527–552.PubMedGoogle Scholar
- Gao ZG, Jacobson KA: Emerging adenosine receptor agonists. Expert Opin Emerg Drugs 2007, 12: 479–492. 10.1517/1472822.214.171.1249View ArticlePubMedGoogle Scholar
- Gao ZG, Mamedova LK, Chen P, Jacobson KA: 2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors. Biochem Pharmacol 2004, 68: 1985–1993. 10.1016/j.bcp.2004.06.011PubMed CentralView ArticlePubMedGoogle Scholar
- Halgren TA: Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 1996, 17: 490–519. 10.1002/(SICI)1096-987X(199604)17:5/6<490::AID-JCC1>3.0.CO;2-PView ArticleGoogle Scholar
- Halgren TA: Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. J Comput Chem 1996, 17: 520–552. 10.1002/(SICI)1096-987X(199604)17:5/6<520::AID-JCC2>3.0.CO;2-WView ArticleGoogle Scholar
- Halgren TA: Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94. J Comput Chem 1996, 17: 553–586. 10.1002/(SICI)1096-987X(199604)17:5/6<553::AID-JCC3>3.0.CO;2-TView ArticleGoogle Scholar
- Halgren TA: Merck molecular force field. IV. Conformational energies and geometries for MMFF94. J Comput Chem 1996, 17: 587–615.Google Scholar
- Halgren TA: MMFF VI. MMFF94s option for energy minimization studies. J Comput Chem 1999, 20: 720–729. 10.1002/(SICI)1096-987X(199905)20:7<720::AID-JCC7>3.0.CO;2-XView ArticleGoogle Scholar
- Halgren TA: MMFF VII. Characterization of MMFF94, MMFF94s, and other widely available force fields for conformational energies and for intermolecular-interaction energies and geometries. J Comput Chem 1999, 20: 730–748. 10.1002/(SICI)1096-987X(199905)20:7<730::AID-JCC8>3.0.CO;2-TView ArticleGoogle Scholar
- Halgren TA, Nachbar R: Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rules. J Comput Chem 1996, 17: 616–641. 10.1002/(SICI)1096-987X(199604)17:5/6<616::AID-JCC5>3.0.CO;2-XView ArticleGoogle Scholar
- Hino T, Arakawa T, Iwanari H, Yurugi-Kobayashi T, Ikeda-Suno C, Nakada-Nakura Y, Kusano-Arai O, Weyand S, Shimamura T, Nomura N, Cameron AD, Kobayashi T, Hamakubo T, Iwata S, Murata T: G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature 2012, 482: 237–240.PubMed CentralPubMedGoogle Scholar
- Hinschen AK, Rose’Meyer RB, Headrick JP: Adenosine receptor subtypes mediating coronary vasodilation in rat hearts. J Cardiovasc Pharmacol 2003, 41: 73–80. 10.1097/00005344-200301000-00010View ArticlePubMedGoogle Scholar
- Inamdar GS, Pandya AN, Thakar HM, Sudarsanam V, Kachler S, Sabbadin D, Moro S, Klotz K-N, Vasu KK: New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides. Eur J Med Chem 2013, 63: 924–934.View ArticlePubMedGoogle Scholar
- Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, IJzerman AP, Stevens RC: The 2.6 angstrom crystal structure of a human A 2A adenosine receptor bound to an antagonist. Science 2008, 322: 1211–1217. 10.1126/science.1164772PubMed CentralView ArticlePubMedGoogle Scholar
- Kemp BK, Cocks TM: Adenosine mediates relaxation of human small resistance-like coronary arteries via A 2B receptors. Br J Pharmacol 1999, 126: 1796–1800. 10.1038/sj.bjp.0702462PubMed CentralView ArticlePubMedGoogle Scholar
- Kreckler LM, Wan TC, Ge ZD, Auchampach JA: Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A 2A and A 2B but not the A 3 adenosine receptor. J Pharmacol Exp Ther 2006, 317: 172–180.View ArticlePubMedGoogle Scholar
- Kuno A, Critz SD, Cui L, Solodushko V, Yang XM, Krahn T, Albrecht B, Philipp S, Cohen MV, Downey JM: Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A 2B -dependent signaling during early reperfusion. J Mol Cell Cardiol 2007, 43: 262–271. 10.1016/j.yjmcc.2007.05.016PubMed CentralView ArticlePubMedGoogle Scholar
- Lambertucci C, Volpini R, Costanzi S, Taffi S, Vittori S, Cristalli G: 2-Phenylhydroxypropynyladenosine derivatives as high potent agonists at A 2B adenosine receptor subtype. Nucleos Nucleot Nucl Acids 2003, 22: 809–812. 10.1081/NCN-120022640View ArticleGoogle Scholar
- Lane JR, Klein Herenbrink C, van Westen GJ, Spoorendonk JA, Hoffmann C, IJzerman AP: A novel nonribose agonist, LUF5834, engages residues that are distinct from those of adenosine-like ligands to activate the adenosine A 2A receptor. Mol Pharmacol 2012, 81: 475–487. 10.1124/mol.111.075937View ArticlePubMedGoogle Scholar
- Lebon G, Warne T, Edwards PC, Bennett K, Langmead CJ, Leslie AG, Tate CG: Agonist-bound adenosine A 2A receptor structures reveal common features of GPCR activation. Nature 2011, 474: 521–525. 10.1038/nature10136PubMed CentralView ArticlePubMedGoogle Scholar
- Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC: Structural basis for allosteric regulation of GPCRs by sodium ions. Science 2012, 337: 232–236. 10.1126/science.1219218PubMed CentralView ArticlePubMedGoogle Scholar
- Molecular Operating Environment C.C.G., Inc: 1255 University St., Suite 1600. Montreal, Quebec, Canada: H3B 3X3;
- Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV: Postconditioning protects rabbit hearts through a protein kinase C-adenosine A 2B receptor cascade. Cardiovasc Res 2006, 70: 308–314. 10.1016/j.cardiores.2006.02.014View ArticlePubMedGoogle Scholar
- Robeva AS, Woodard RL, Jin X, Gao Z, Bhattacharya S, Taylor HE, Rosin DL, Linden J: Molecular characterization of recombinant human adenosine receptors. Drug Dev Res 1996, 39: 243–252. 10.1002/(SICI)1098-2299(199611/12)39:3/4<243::AID-DDR3>3.0.CO;2-RView ArticleGoogle Scholar
- Rosentreter U, Henning R, Bauser M, Krämer T, Vaupel A, Hübsch W, Dembowsky K, Salcher-Schraufstätter O, Stasch JP, Krahn T, Perzborn E: Substituted 2-Thio-3,5-Dicyano-4-Aryl-6-Aminopyridines and the use Thereof as Adenosine Receptor Ligands. 2001. WO/2001/025210Google Scholar
- Rosentreter U, Kraemer T, Shimada M, Huebsch W, Diedrichs N, Krahn T, Henninger K, Stasch JP: Substituted 2-Thio-3,5-Dicyano-4-Phenyl-6-Aminopyridines and their use as Adenosine Receptor-Selective Ligands. 2003. WO/2003/008384Google Scholar
- Schiedel AC, Hinz S, Thimm D, Sherbiny F, Borrmann T, Maass A, Müller CE: The four cysteine residues in the second extracellular loop of the human adenosine A 2B receptor: role in ligand binding and receptor function. Biochem Pharmacol 2011, 82: 389–399. 10.1016/j.bcp.2011.05.008View ArticlePubMedGoogle Scholar
- Shadnia H, Wright JS, Anderson JM: Interaction force diagrams: new insight into ligand-receptor binding. J Comput Aided Mol Des 2009, 23: 185–194. 10.1007/s10822-008-9250-3View ArticlePubMedGoogle Scholar
- Sherbiny FF, Schiedel AC, Maass A, Müller CE: Homology modelling of the human adenosine A 2B receptor based on X-ray structures of bovine rhodopsin, the β 2 -adrenergic receptor and the human adenosine A 2A receptor. J Comput Aided Mol Des 2009, 23: 807–828. 10.1007/s10822-009-9299-7View ArticlePubMedGoogle Scholar
- Stewart JJ: MOPAC: a semiempirical molecular orbital program. J Comput Aided Mol Des 1990, 4: 1–105. 10.1007/BF00128336View ArticlePubMedGoogle Scholar
- Thimm D, Schiedel AC, Sherbiny FF, Hinz S, Hochheiser K, Bertarelli DCG, Maass A, Müller CE: Ligand-specific binding and activation of the human adenosine A 2B receptor. Biochemistry 2013, 52: 726–740. 10.1021/bi3012065View ArticlePubMedGoogle Scholar
- van der Hoeven D, Wan TC, Gizewski ET, Kreckler LM, Maas JE, Van Orman J, Ravid K, Auchampach JA: A role for the low-affinity A 2B adenosine receptor in regulating superoxide generation by murine neutrophils. J Pharmacol Exp Ther 2011, 338: 1004–1012. 10.1124/jpet.111.181792PubMed CentralView ArticlePubMedGoogle Scholar
- Volpini R, Costanzi S, Lambertucci C, Taffi S, Vittori S, Klotz KN, Cristalli G: N 6 -alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A 3 receptor and a starting point for searching A 2B ligands. J Med Chem 2002, 45: 3271–3279. 10.1021/jm0109762View ArticlePubMedGoogle Scholar
- Volpini R, Costanzi S, Vittori S, Cristalli G, Klotz K-N: Medicinal chemistry and pharmacology of A 2B adenosine receptors. Curr Top Med Chem 2003, 3: 427–443. 10.2174/1568026033392264View ArticlePubMedGoogle Scholar
- Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC: Structure of an agonist-bound human A 2A adenosine receptor. Science 2011, 332: 322–327. 10.1126/science.1202793PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.