Molecular Basis of Modulating Adenosine Receptors Activities

Author(s): Mohammed Nooraldeen Mahmod Al-Qattan*, Mohd Nizam Mordi*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 7 , 2019

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Modulating cellular processes through extracellular chemical stimuli is medicinally an attractive approach to control disease conditions. GPCRs are the most important group of transmembranal receptors that produce different patterns of activations using intracellular mediators (such as G-proteins and Beta-arrestins). Adenosine receptors (ARs) belong to GPCR class and are divided into A1AR, A2AAR, A2BAR and A3AR. ARs control different physiological activities thus considered valuable target to control neural, heart, inflammatory and other metabolic disorders. Targeting ARs using small molecules essentially works by binding orthosteric and/or allosteric sites of the receptors. Although targeting orthosteric site is considered typical to modulate receptor activity, allosteric sites provide better subtype selectivity, saturable modulation of activity and variable activation patterns. Each receptor exists in dynamical equilibrium between conformational ensembles. The equilibrium is affected by receptor interaction with other molecules. Changing the population of conformational ensembles of the receptor is the method by which orthosteric, allosteric and other cellular components control receptor signaling. Herein, the interactions of ARs with orthosteric, allosteric ligands as well as intracellular mediators are described. A quinary interaction model for the receptor is proposed and energy wells for major conformational ensembles are retrieved.

Keywords: Adenosine receptor, GPCR, orthosteric, allosteric ligands, modulators, receptor conformations, interaction model.

Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006; 5(3): 247-64.
Pran Kishore D, Balakumar C, Raghuram Rao A, Roy PP, Roy K. QSAR of adenosine receptor antagonists: Exploring physicochemical requirements for binding of pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine derivatives with human adenosine A(3) receptor subtype. Bioorg Med Chem Lett 2011; 21(2): 818-23.
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.
Chen JF, Eltzschig HK, Fredholm BB. Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 2013; 12(4): 265-86.
Fredholm BB. Adenosine--a physiological or pathophysiological agent? J Mol Med (Berl) 2014; 92(3): 201-6.
Haskó G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 2008; 7(9): 759-70.
Fredholm BB, Irenius E, Kull B, Schulte G. Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 2001; 61(4): 443-8.
Fredholm BB. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 2007; 14(7): 1315-23.
Gao Z-G, Tosh DK, Jain S, Yu J, Suresh RR, Jacobson KAA A. 1 adenosine receptor agonists, antagonists, and allosteric modulators Springer 2018; 59-89.
Chandrasekaran B, Deb PK, Kachler S, Akkinepalli RR, Mailavaram R, Klotz K-N. 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.
Deb PK, Mailavaram R, Chandrasekaran B, et al. Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno [2,3-d]pyrimidine derivatives. Chem Biol Drug Des 2018; 91(4): 962-9.
Pirovano IM, IJzerman AP, Van Galen PJ, Soudijn W. Influence of the molecular structure of N6-(omega-aminoalkyl)adenosines on adenosine receptor affinity and intrinsic activity. Eur J Pharmacol 1989; 172(2): 185-93.
Gessi S, Merighi S, Varani K. Adenosine Receptors: The Status of the ArtSpringer International Publishing: Cham2018; 1-11
Thomas RL, Mistry R, Langmead CJ, Wood MD, Challiss RAJ. G protein coupling and signaling pathway activation by m1 muscarinic acetylcholine receptor orthosteric and allosteric agonists. J Pharmacol Exp Ther 2008; 327(2): 365-74.
La Motta C, Sartini S, Morelli M, Taliani S, Da Settimo F. Allosteric modulators for adenosine receptors: an alternative to the orthosteric ligands. Curr Top Med Chem 2010; 10(10): 976-92.
Christopoulos A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 2002; 1(3): 198-210.
May LT, Leach K, Sexton PM, Christopoulos A. Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 2007; 47: 1-51.
Mailman RB. GPCR functional selectivity has therapeutic impact rends Pharmacol Sci 2007 28: 390-6.
Rankovic Z, Brust TF, Bohn LM. Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett 2016; 26(2): 241-50.
Luttrell LM. Minireview: More than just a hammer: ligand “bias” and pharmaceutical discovery. Mol Endocrinol 2014; 28(3): 281-94.
Luttrell LM, Maudsley S, Bohn LM. Fulfilling the Promise of ‘Biased’ GPCR Agonism. Mol Pharmacol 2015.
Baltos JA, Paoletta S, Nguyen AT, et al. Structure-activity analysis of biased agonism at the human adenosine A3 receptor. Mol Pharmacol 2016; 90(1): 12-22.
Baltos J-A, Gregory KJ, White PJ, Sexton PM, Christopoulos A, May LT. Quantification of adenosine A(1) receptor biased agonism: Implications for drug discovery. Biochem Pharmacol 2016; 99: 101-12.
Vecchio EA, Baltos JA, Nguyen ATN, Christopoulos A, White PJ, May LT. New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism. Br J Pharmacol 2018; 175(21): 4036-46.
Draper-Joyce CJ, Khoshouei M, Thal DM, et al. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 2018; 558(7711): 559-63.
Cheng RKY, Segala E, Robertson N, et al. Structures of human A1 and A2A adenosine receptors with xanthines reveal determinants of selectivity structure 1993; 2017; 25: 1275-1285.e4.
Glukhova A, Thal DM, Nguyen AT, et al. Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 2017; 168(5): 867-877.e13.
Manglik A, Kruse AC. Structural basis for G protein-coupled receptor activation. Biochemistry 2017; 56(42): 5628-34.
Lebon G, Warne T, Edwards PC, et al. Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 2011; 474(7352): 521-5.
García-Nafría J, Lee Y, Bai X, Carpenter B, Tate CG. Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein. eLife 2018; 7: 7.
Carpenter B, Nehmé R, Warne T, Leslie AGW, Tate CG. Erratum: Structure of the adenosine A2A receptor bound to an engineered G protein. Nature 2016; 538(7626): 542.
Ijzerman AP, Von Frijtag Drabbe Künzel JK, Kim J, Jiang Q, Jacobson KA. Site-directed mutagenesis of the human adenosine A(2A) receptor. Critical involvement of Glu(13) in agonist recognition. Biochem Pharmacol 2000; 60: 661-8.
Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S. Action of molecular switches in GPCRs--theoretical and experimental studies. Curr Med Chem 2012; 19(8): 1090-109.
Lee Y, Choi S, Hyeon C. Communication over the network of binary switches regulates the activation of A2A adenosine receptor. PLOS Comput Biol 2015; 11(2)e1004044
Jespers W, Schiedel AC, Heitman LH, et al. Structural mapping of adenosine receptor mutations: ligand binding and signaling mechanisms. Trends Pharmacol Sci 2018; 39(1): 75-89.
Jin X, Shepherd RK, Duling BR, Linden J. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J Clin Invest 1997; 100(11): 2849-57.
Welihinda AA, Kaur M, Greene K, Zhai Y, Amento EP. The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias. Cell Signal 2016; 28(6): 552-60.
Congreve M, Andrews SP, Doré AS, et al. Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design. J Med Chem 2012; 55(5): 1898-903.
Poucher SM, Keddie JR, Singh P, et al. The in vitro pharmacology of ZM 241385, a potent, non-xanthine A2a selective adenosine receptor antagonist. Br J Pharmacol 1995; 115(6): 1096-102.
Fredholm BB, Persson CGA. Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 1982; 81(4): 673-6.
Carpenter B, Lebon G. Human adenosine A2A receptor: Molecular mechanism of ligand binding and activation. Front Pharmacol 2017; 8: 898.
Portoghese PS, Sultana M, Nagase H, Takemori AE. Application of the message-address concept in the design of highly potent and selective non-peptide delta opioid receptor antagonists. J Med Chem 1988; 31(2): 281-2.
Jacobson KA, Gao Z-G, Paoletta S, et al. John daly lecture: structure-guided drug design for adenosine and P2Y receptors. Comput Struct Biotechnol J 2014; 13: 286-98.
Bharate SB, Singh B, Kachler S, et al. Discovery of 7-(prolinol-N-yl)-2-phenylamino-thiazolo [5,4-d]pyrimidines as novel non-nucleoside partial agonists for the A2A adenosine receptor: prediction from molecular modeling. J Med Chem 2016; 59(12): 5922-8.
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(3): 475-87.
Segala E, Guo D, Cheng RKY, et al. Controlling the dissociation of ligands from the adenosine A2A receptor through modulation of salt bridge strength. J Med Chem 2016; 59(13): 6470-9.
Hothersall JD, Guo D, Sarda S, et al. Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics. Mol Pharmacol 2017; 91(1): 25-38.
Peeters MC, Wisse LE, Dinaj A, Vroling B, Vriend G, Ijzerman AP. The role of the second and third extracellular loops of the adenosine A1 receptor in activation and allosteric modulation. Biochem Pharmacol 2012; 84(1): 76-87.
Deganutti G, Welihinda A, Moro S. Comparison of the human A2A adenosine receptor recognition by adenosine and inosine: New insight from supervised molecular dynamics simulations. ChemMedChem 2017; 12(16): 1319-26.
Matricon P, Ranganathan A, Warnick E, et al. Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site. Sci Rep 2017; 7(1): 6398.
Al-Qattan MN, Deb PK, Tekade RK. Molecular dynamics simulation strategies for designing carbon-nanotube-based targeted drug delivery. Drug Discov Today 2018; 23(2): 235-50.
Deb PK, Al-Attraqchi O, Al-Qattan MN, Raghu Prasad M, Tekade RK. Chapter 19 - applications of computers in pharmaceutical product formulation. InTekade RK. 2018; 665-703.
Christopoulos A, Changeux J-P, Catterall WA, et al. International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev 2014; 66(4): 918-47.
Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW. Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol 2014; 54: 165-84.
Schrage R, Kostenis E. Functional selectivity and dualsteric/bitopic GPCR targeting. Curr Opin Pharmacol 2017; 32: 85-90.
Valant C, Robert Lane J, Sexton PM, Christopoulos A. The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol 2012; 52: 153-78.
Guo D, Heitman LH, IJzerman AP. Kinetic aspects of the interaction between ligand and G protein-coupled receptor: The case of the adenosine receptors. Chem Rev 2017; 117(1): 38-66.
Hill SJ, May LT, Kellam B, Woolard J. Allosteric interactions at adenosine A(1) and A(3) receptors: new insights into the role of small molecules and receptor dimerization. Br J Pharmacol 2014; 171(5): 1102-13.
May LT, Bridge LJ, Stoddart LA, Briddon SJ, Hill SJ. Allosteric interactions across native adenosine-A3 receptor homodimers: quantification using single-cell ligand-binding kinetics. FASEB J 2011; 25(10): 3465-76.
Ye L, Neale C, Sljoka A, et al. Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations. Nat Commun 2018; 9(1): 1372.
Guixà-González R, Albasanz JL, Rodriguez-Espigares I, et al. Membrane cholesterol access into a G-protein-coupled receptor. Nat Commun 2017; 8: 14505.
Brady AE, Limbird LE. G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction. Cell Signal 2002; 14(4): 297-309.
van der Westhuizen ET, Valant C, Sexton PM, Christopoulos A. Endogenous allosteric modulators of G protein-coupled receptors. J Pharmacol Exp Ther 2015; 353(2): 246-60.
Bruzzese A, Gil C, Dalton JAR, Giraldo J. Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions. Sci Rep 2018; 8(1): 4456.
Boyhus L-E, Danielsen M, Bengtson NS, et al. Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor. RSC Advances 2018; 8: 2219-28.
Christopoulos A, Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol Rev 2002; 54(2): 323-74.
Hebert TE, Moffett S, Morello JP, et al. A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem 1996; 271(27): 16384-92.
Deganutti G, Salmaso V, Moro S. Could adenosine recognize its receptors with a stoichiometry other than 1 : 1? Mol Inform 2018; 37(8)e1800009
Kenakin T. New lives for seven transmembrane receptors as drug targets trends. Pharmacol Sci 2015; 36: 705-6.
Lu S, Zhang J. Small molecule allosteric modulators of G-protein-coupled receptors: drug-target interactions. J Med Chem 2018.
Kruse AC, Ring AM, Manglik A, et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 2013; 504(7478): 101-6.
Liu X, Ahn S, Kahsai AW, et al. Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature 2017; 548(7668): 480-4.
Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 2011; 1808(5): 1290-308.
Lu S, Huang W, Zhang J. Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today 2014; 19(10): 1595-600.
Lu S, Ji M, Ni D, Zhang J. Discovery of hidden allosteric sites as novel targets for allosteric drug design. Drug Discov Today 2018; 23(2): 359-65.
Deganutti G, Moro S. Supporting the identification of novel fragment-based positive allosteric modulators using a supervised molecular dynamics approach: a retrospective analysis considering the human A2A adenosine receptor as a key example. Molecules 2017; 22(5): 818.
Caliman AD, Miao Y, McCammon JA. Mapping the allosteric sites of the A2A adenosine receptor. Chem Biol Drug Des 2018; 91(1): 5-16.
Ivetac A, McCammon JA. Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach. Chem Biol Drug Des 2010; 76(3): 201-17.
Vaidehi N, Bhattacharya S. Allosteric communication pipelines in G-protein-coupled receptors. Curr Opin Pharmacol 2016; 30: 76-83.
Yang L. Cholesterol Interactions with the A2A adenosine receptor: all-atom, coarse-grained, and metadynamics simulations. Biophys J 2018; 114: 275a.
Narlawar R, Lane JR, Doddareddy M, Lin J, Brussee J, Ijzerman AP. Hybrid ortho/allosteric ligands for the adenosine A(1) receptor. J Med Chem 2010; 53(8): 3028-37.
Sun B, Bachhawat P, Chu ML, et al. Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket. Proc Natl Acad Sci USA 2017; 114(8): 2066-71.
Nguyen AT, Baltos JA, Thomas T, et al. Extracellular loop 2 of the adenosine A1 receptor has a key role in orthosteric ligand affinity and agonist efficacy. Mol Pharmacol 2016; 90(6): 703-14.
Kennedy DP, McRobb FM, Leonhardt SA, et al. The second extracellular loop of the adenosine A1 receptor mediates activity of allosteric enhancers. Mol Pharmacol 2014; 85(2): 301-9.
Costa-Neto CM. Parreiras-E-Silva LT, Bouvier M. A pluridimensional view of biased agonism. Mol Pharmacol 2016; 90(5): 587-95.
Dror RO, Pan AC, Arlow DH, et al. Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc Natl Acad Sci USA 2011; 108(32): 13118-23.
Guo D, Pan AC, Dror RO, et al. Molecular basis of ligand dissociation from the adenosine A2A receptor. Mol Pharmacol 2016; 89(5): 485-91.
Nguyen AT, Vecchio EA, Thomas T, et al. The role of the second extracellular loop of the adenosine A1 receptor on allosteric modulator binding, signaling and cooperativity. Mol Pharmacol 2016; 90(6): 715-25.
Göblyös A, Ijzerman AP. Allosteric modulation of adenosine receptors. Biochim Biophys Acta 2011; 1808(5): 1309-18.
Liu W, Chun E, Thompson AA, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science 2012; 337(6091): 232-6.
Gutierrez-de-Teran H, Massink A, Rodriguez D, et al. The role of a sodium ion binding site in the allosteric modulation of the A(2A) adenosine G protein-coupled receptor Structure (London, England : 1993) 2013; 21: 2175-85.
Massink A, Louvel J, Adlere I, et al. 5′-substituted amiloride derivatives as allosteric modulators binding in the sodium ion pocket of the adenosine A2A receptor. J Med Chem 2016; 59(10): 4769-77.
Gao ZG, Ijzerman AP. Allosteric modulation of A(2A) adenosine receptors by amiloride analogues and sodium ions. Biochem Pharmacol 2000; 60(5): 669-76.
Gao Z-G, Melman N, Erdmann A, et al. Differential allosteric modulation by amiloride analogues of agonist and antagonist binding at A(1) and A(3) adenosine receptors. Biochem Pharmacol 2003; 65(4): 525-34.
Göblyös A, de Vries H, Brussee J, Ijzerman AP. Synthesis and biological evaluation of a new series of 2,3,5-substituted [1,2,4]-thiadiazoles as modulators of adenosine A1 receptors and their molecular mechanism of action. J Med Chem 2005; 48(4): 1145-51.
Zhou XE, Melcher K, Xu HE. Understanding the GPCR biased signaling through G protein and arrestin complex structures. Curr Opin Struct Biol 2017; 45: 150-9.
Yao X-Q, Cato MC, Labudde E, Beyett TS, Tesmer JJG, Grant BJ. Navigating the conformational landscape of G protein-coupled receptor kinases during allosteric activation. J Biol Chem 2017; 292(39): 16032-43.
Eichel K, von Zastrow M. Subcellular Organization of GPCR Signaling rends Pharmacol Sci 2018. 39: 200-8.
Thomsen ARB, Plouffe B, Cahill TJ III, et al. GPCR-G protein-β-arrestin super-complex mediates sustained G protein signaling. Cell 2016; 166(4): 907-19.
Walther C, Ferguson SSG. Minireview: Role of intracellular scaffolding proteins in the regulation of endocrine G protein-coupled receptor signaling. Mol Endocrinol 2015; 29(6): 814-30.
Hilger D, Masureel M, Kobilka BK. Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol 2018; 25(1): 4-12.
Melancon BJ, Hopkins CR, Wood MR, et al. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem 2012; 55(4): 1445-64.
Schwartz TW, Holst B. Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? Trends Pharmacol Sci 2007; 28: 366-73.
Lane JR, May LT, Parton RG, Sexton PM, Christopoulos A. A kinetic view of GPCR allostery and biased agonism. Nat Chem Biol 2017; 13(9): 929-37.
Szczepek M, Beyrière F, Hofmann KP, et al. Crystal structure of a common GPCR-binding interface for G protein and arrestin. Nat Commun 2014; 5: 4801.
Ranjan R, Dwivedi H, Baidya M, Kumar M, Shukla AK. Novel structural insights into GPCR-β-arrestin interaction and signaling. Trends Cell Biol 2017; 27(11): 851-62.
Storme J, Cannaert A, Van Craenenbroeck K, Stove CP. Molecular dissection of the human A3 adenosine receptor coupling with β-arrestin2. Biochem Pharmacol 2018; 148: 298-307.
Shukla AK, Westfield GH, Xiao K, et al. Visualization of arrestin recruitment by a G-protein-coupled receptor. Nature 2014; 512(7513): 218-22.
Sente A, Peer R, Srivastava A, et al. Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation. Nat Struct Mol Biol 2018; 25(6): 538-45.
Yang Z, Yang F, Zhang D, et al. Phosphorylation of G Protein-Coupled Receptors: From the Barcode Hypothesis to the Flute Model. Mol Pharmacol 2017; 92(3): 201-10.
Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 2018; 17(4): 243-60.
Monod J, Wyman J, Changeux JPON. On the nature of allosteric transitions: A plausible model. J Mol Biol 1965; 12: 88-118.
Hall DA. Modeling the functional effects of allosteric modulators at pharmacological receptors: an extension of the two-state model of receptor activation. Mol Pharmacol 2000; 58(6): 1412-23.
Deupi X, Kobilka BK. Energy landscapes as a tool to integrate GPCR structure, dynamics, and function. Physiology 2010; 25(5): 293-303.
Xiang J, Chun E, Liu C, et al. Successful Strategies to Determine High-Resolution Structures of GPCRs rends Pharmacol Sci 2016. 37: 1055-69
Robertson N, Jazayeri A, Errey J, et al. The properties of thermostabilised G protein-coupled receptors (StaRs) and their use in drug discovery. Neuropharmacology 2011; 60(1): 36-44.
Vincenzi F, Varani K, Borea PA. Binding Thermodynamic Characteristics of Adenosine Receptor Ligands.PA Borea, K Varani, S Gessi, S Merighi, F Vincenzi. 2018; Springer International Publishing: Cham199-215.
Yuan S, Filipek S, Palczewski K, Vogel H. Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway. Nat Commun 2014; 5: 4733.
Yuan S, Hu Z, Filipek S, Vogel H. W246(6.48) opens a gate for a continuous intrinsic water pathway during activation of the adenosine A2A receptor. Angew Chem Int Ed Engl 2015; 54(2): 556-9.
Rasmussen SGF, Choi H-J, Fung JJ, et al. Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature 2011; 469(7329): 175-80.
Xu F, Wu H, Katritch V, et al. Structure of an agonist-bound human A2A adenosine receptor. Science 2011; 332(6027): 322-7.
White KL, Eddy MT, Gao ZG, et al. Structural connection between activation microswitch and allosteric sodium site in gpcr signaling structure (London, England : 1993) 2018; 26: 259-269.e5.
Vickery ON, Carvalheda CA, Zaidi SA, Pisliakov AV, Katritch V, Zachariae U. Intracellular transfer of Na(+) in an active-state Gprotein- coupled receptor structure (London, England : 1993) 2018; 26: 171-180.e2
Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC. Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 2014; 39(5): 233-44.
Wheatley M, Wootten D, Conner MT, et al. Lifting the lid on GPCRs: the role of extracellular loops. Br J Pharmacol 2012; 165(6): 1688-703.
Ye L, Van Eps N, Zimmer M, Ernst OP, Prosser RS. Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 2016; 533(7602): 265-8.
Prosser RS, Ye L, Pandey A, Orazietti A. Activation processes in ligand-activated G protein-coupled receptors: A case study of the adenosine A2A receptor. BioEssays 2017; 39(9)1700072
Manglik A, Kim TH, Masureel M, et al. Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 2015; 161(5): 1101-11.
Eddy MT, Lee M-Y, Gao Z-G, et al. Allosteric coupling of drug binding and intracellular signaling in the A2A adenosine receptor. Cell 2018; 172(1-2): 68-80.e12.
Lee JY, Lyman E. Agonist dynamics and conformational selection during microsecond simulations of the A(2A) adenosine receptor. Biophys J 2012; 102(9): 2114-20.
Katritch V, Cherezov V, Stevens RC. Diversity and modularity of G protein-coupled receptor structures rends Pharmacol Sci 2012. 33: 17-27.
Bhattacharya S, Vaidehi N. Differences in allosteric communication pipelines in the inactive and active states of a GPCR. Biophys J 2014; 107(2): 422-34.
Clark LD, Dikiy I, Chapman K, et al. Ligand modulation of sidechain dynamics in a wild-type human GPCR. eLife 2017; 6: 6.
Carpenter B, Tate CG. Engineering a minimal G protein to facilitate crystallisation of G protein-coupled receptors in their active conformation. Protein Eng Des Sel 2016; 29(12): 583-94.
Murphree LJ, Marshall MA, Rieger JM, MacDonald TL, Linden J. Human A(2A) adenosine receptors: high-affinity agonist binding to receptor-G protein complexes containing Gbeta(4). Mol Pharmacol 2002; 61(2): 455-62.
DeVree BT, Mahoney JP, Vélez-Ruiz GA, et al. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 2016; 535(7610): 182-6.
Gao Z-G, Van Muijlwijk-Koezen JE, Chen A, Müller CE, Ijzerman AP, Jacobson KA. Allosteric modulation of A(3) adenosine receptors by a series of 3-(2-pyridinyl)isoquinoline derivatives. Mol Pharmacol 2001; 60(5): 1057-63.
Bruns RF, Fergus JH. Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes. Mol Pharmacol 1990; 38(6): 939-49.
Kourounakis A, Visser C, de Groote M, IJzerman AP. Differential effects of the allosteric enhancer (2-amino-4,5-dimethyl-trienyl)[3-trifluoromethyl) phenyl]methanone (PD81,723) on agonist and antagonist binding and function at the human wild-type and a mutant (T277A) adenosine A1 receptor. Biochem Pharmacol 2001; 61(2): 137-44.
Gao Z-G, Ye K, Göblyös A, Ijzerman AP, Jacobson KA. Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000. BMC Pharmacol 2008; 8: 20-0.
Deganutti G, Cuzzolin A, Ciancetta A, Moro S. Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000. Bioorg Med Chem 2015; 23(14): 4065-71.
Miao Y, Bhattarai A, Nguyen ATN, Christopoulos A, May LT. Structural basis for binding of allosteric drug leads in the adenosine A1 receptor. Sci Rep 2018; 8(1): 16836.
Dror RO, Green HF, Valant C, et al. Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 2013; 503(7475): 295-9.
Baraldi PG, Iaconinoto MA, Moorman AR, et al. Allosteric enhancers for A1 adenosine receptor. Mini Rev Med Chem 2007; 7(6): 559-69.
Wootten D, Savage EE, Valant C, et al. Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol 2012; 82(2): 281-90.
Valant C, Felder CC, Sexton PM, Christopoulos A. Probe dependence in the allosteric modulation of a G protein-coupled receptor: implications for detection and validation of allosteric ligand effects. Mol Pharmacol 2012; 81(1): 41-52.
Pietra D, Borghini A, Breschi MC, Bianucci AM. Enhancer and competitive allosteric modulation model for G-protein-coupled receptors. J Theor Biol 2010; 267(4): 663-75.
Wold EA, Chen J, Cunningham KA, Zhou J. Allosteric modulation of class A GPCRs: Targets, agents, and emerging concepts. J Med Chem 2018.
Avlani V, May LT, Sexton PM, Christopoulos A. Application of a kinetic model to the apparently complex behavior of negative and positive allosteric modulators of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 2004; 308(3): 1062-72.
Kenakin T. Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 2011; 336(2): 296-302.
Stallaert W, Christopoulos A, Bouvier M. Ligand functional selectivity and quantitative pharmacology at G protein-coupled receptors. Expert Opin Drug Discov 2011; 6(8): 811-25.
Wisler JW, DeWire SM, Whalen EJ, et al. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci USA 2007; 104(42): 16657-62.
Leach K, Sexton PM, Christopoulos A. Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol Sci 2007; 28(8): 382-9.
Violin JD, Lefkowitz RJ. β-Arrestin-biased ligands at seventransmembrane receptors rends Pharmacol Sci 2007; 28: 416-22.
Khoury E, Clément S, Laporte SA. Allosteric and biased g protein-coupled receptor signaling regulation: potentials for new therapeutics. Front Endocrinol (Lausanne) 2014; 5: 68.
Bologna Z, Teoh JP, Bayoumi AS, Tang Y, Kim IM, Biased G. Biased G protein-coupled receptor signaling: new player in modulating physiology and pathology. Biomol Ther (Seoul) 2017; 25(1): 12-25.
Kenakin T. Is the Quest for Signaling Bias Worth the Effort? Mol Pharmacol 2018; 93(4): 266-9.
de Ligt RA, Rivkees SA, Lorenzen A, Leurs R, IJzerman APA. “locked-on,” constitutively active mutant of the adenosine A1 receptor. Eur J Pharmacol 2005; 510(1-2): 1-8.
Barbhaiya H, McClain R, Ijzerman A, Rivkees SA. Site-directed mutagenesis of the human A1 adenosine receptor: influences of acidic and hydroxy residues in the first four transmembrane domains on ligand binding. Mol Pharmacol 1996; 50(6): 1635-42.
Gao Z-G, Jiang Q, Jacobson KA, Ijzerman AP. Site-directed mutagenesis studies of human A(2A) adenosine receptors: involvement of glu(13) and his(278) in ligand binding and sodium modulation. Biochem Pharmacol 2000; 60(5): 661-8.
Gao Z-G, Kim S-K, Gross AS, Chen A, Blaustein JB, Jacobson KA. Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor. Mol Pharmacol 2003; 63(5): 1021-31.

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Article Details

Year: 2019
Published on: 16 June, 2019
Page: [817 - 831]
Pages: 15
DOI: 10.2174/1381612825666190304122624
Price: $65

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