Skip to main content
SpringerLink
Log in

A1 Adenosine Receptor Agonists, Antagonists, and Allosteric Modulators

  • Chapter
  • First Online:
The Adenosine Receptors

Part of the book series: The Receptors ((REC,volume 34))

Abstract

One of the four G protein-coupled receptors for adenosine, the A1 adenosine receptors (A1AR), is widely distributed in the body and modulates numerous normal and pathological processes, through signaling pathways including those downstream from its coupled Gi protein. It is an attractive drug target for heart failure, arrhythmias, angina, asthma, stroke, seizure, pain, depression, and diabetes. In this chapter, we describe the A1AR structure, function, signaling pathways, and therapeutic applications. We detail numerous structure-activity features of A1AR agonists, antagonists, and allosteric modulators, introduced as pharmacological tools and molecules for clinical development.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alachouzos G, Lenselink EB, Mulder-Krieger T et al (2017) Synthesis and evaluation of N-substituted 2-amino-4,5-diarylpyrimidines as selective adenosine A1 receptor antagonists. Eur J Med Chem 125:586–602

    Article  PubMed  CAS  Google Scholar 

  • Albrecht-Küpper BE, Leineweber K, Nell PG (2012) Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic Signal 8(Suppl 1):91–99

    Article  PubMed  CAS  Google Scholar 

  • Alexander SP (2006) Flavonoids as antagonists at A1 adenosine receptors. Phytother Res 20(11):1009–1012

    Article  PubMed  CAS  Google Scholar 

  • Alnouri MW, Jepards S, Casari A et al (2015) Selectivity is species-dependent: characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors. Purinergic Signal 11:389–407

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Amorim BO, Hamani C, Ferreira E et al (2016) Effects of A1 receptor agonist/antagonist on spontaneous seizures in pilocarpine-induced epileptic rats. Epilepsy Behav 61:168–173

    Article  PubMed  Google Scholar 

  • Andoh T, Kobayashi N, Uta D et al (2017) Prophylactic topical paeoniflorin prevents mechanical allodynia caused by paclitaxel in mice through adenosine A1 receptors. Phytomedicine 25:1–7

    Article  PubMed  CAS  Google Scholar 

  • Antonioli L, Blandizzi C, Csóka B et al (2015) Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations. Nat Rev Endocrinol 11(4):228–241

    Article  PubMed  CAS  Google Scholar 

  • Araldi D, Ferrari LF, Levine JD (2016) Adenosine-A1 receptor agonist induced hyperalgesic priming type II. Pain 157:698–709

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baltos JA, Gregory KJ, White PJ et al (2016) Quantification of adenosine A1 receptor biased agonism: implications for drug discovery. Biochem Pharmacol 99:101–112

    Article  PubMed  CAS  Google Scholar 

  • Baltos JA, Vecchio EA, Harris MA et al (2017) Capadenoson, a clinically trialed partial adenosine A1 receptor agonist, can stimulate adenosine A2B receptor biased agonism. Biochem Pharmacol 135:79–89

    Article  PubMed  CAS  Google Scholar 

  • Barbhaiya H, McClain R, IJzerman A et al (1996) 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 50(6):1635–1642

    PubMed  CAS  Google Scholar 

  • Barrington WW, Jacobson KA, Stiles GL (1989) Demonstration of distinct agonist and antagonist conformations of the A1 adenosine receptor. J Biol Chem 264:13157–13164

    PubMed  CAS  Google Scholar 

  • Baraldi PG, Iaconinoto MA, Moorman AR, Carrion MD, Cara CL, Preti D, López OC, Fruttarolo F, Tabrizi MA, Romagnoli R (2007) Allosteric enhancers for A1 adenosine receptor. Mini-Rev Med Chem 7:559–569

    Article  PubMed  CAS  Google Scholar 

  • Bauer A, Ishiwata K (2009) Adenosine receptor ligands and PET imaging of the CNS. Handb Exp Pharmacol 193:617–642

    Article  CAS  Google Scholar 

  • Beukers MW, Chang LC, von Frijtag Drabbe Künzel JK et al (2004) New, non-adenosine, high-potency agonists for the human adenosine A2B receptor with an improved selectivity profile compared to the reference agonist N-ethylcarboxamidoadenosine. J Med Chem 47:3707–3709

    Article  PubMed  CAS  Google Scholar 

  • Blum T, Elmert J, Wutz W et al (2004) First no-carrier added radioselenation of an adenosine A1 receptor ligand. J Label Compd Radiopharm 47:415–427

    Google Scholar 

  • Boison D (2007) Adenosine as a modulator of brain activity. Drug News Perspect 20:607–611

    Article  PubMed  CAS  Google Scholar 

  • Borea PA, Gessi S, Merighi S et al (2016) Adenosine as a multi-signalling guardian angel in human diseases: when, where and how does it exert its protective effects? Trends Pharmacol Sci 37:419–434

    Article  CAS  PubMed  Google Scholar 

  • Brundege JM, Dunwiddie TV (1997) Role of adenosine as a modulator of synaptic activity in the central nervous system. Adv Pharmacol 39:353–391

    Article  PubMed  CAS  Google Scholar 

  • Bruns RF, Fergus JH (1990) Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes. Mol Pharmacol 38:939–949

    PubMed  CAS  Google Scholar 

  • Bruns RF, Daly JW, Snyder SH (1980) Adenosine receptors in brain membranes: binding of N6-cyclohexyl[3H]adenosine and 1,3-diethyl-8-[3H]phenylxanthine. Proc Natl Acad Sci U S A 77(9):5547–5551

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bruns RF, Fergus JH, Badger EW et al (1987) Binding of the A1-selective adenosine antagonist 8-cyclopentyl-1,3-dipropylxanthine to rat brain membranes. Naunyn Schmiedeberg’s Arch Pharmacol 335:59–63

    Article  CAS  Google Scholar 

  • Burnstock G (2017) Purinergic Signalling: therapeutic developments. Front Pharmacol 8:661

    Article  PubMed  PubMed Central  Google Scholar 

  • Butcher RW, Sutherland EW (1962) Adenosine 3’,5’-phosphate in biological materials. J Biol Chem 237:1244–1250

    PubMed  CAS  Google Scholar 

  • Cappellacci L, Franchetti P, Pasqualini M et al (2005) Synthesis, biological evaluation, and molecular modeling of ribose-modified adenosine analogues as adenosine receptor agonists. J Med Chem 48(5):1550–1562

    Article  PubMed  CAS  Google Scholar 

  • Carlin JL, Jain S, Gizewski E et al (2017) Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms. Neuropharmacology 114:101–113

    Article  PubMed  CAS  Google Scholar 

  • Chang LC, Spanjersberg RF, von Frijtag Drabbe Künzel JK et al (2004) 2,4,6-trisubstituted pyrimidines as a new class of selective adenosine A1 receptor antagonists. J Med Chem 47(26):6529–6540

    Article  PubMed  CAS  Google Scholar 

  • Chang LC, von Frijtag Drabbe Künzel JK, Mulder-Krieger T et al (2005) A series of ligands displaying a remarkable agonistic-antagonistic profile at the adenosine A1 receptor. J Med Chem 48(6):2045–2053

    Article  PubMed  CAS  Google Scholar 

  • Chen CR, Sun Y, Luo YJ et al (2016) Paeoniflorin promotes non-rapid eye movement sleep via adenosine A1 receptors. J Pharmacol Exp Ther 356(1):64–73

    Article  PubMed  CAS  Google Scholar 

  • Cheng RKY, Segala E, Robertson N et al (2017) Structures of human A1 and A2A adenosine receptors with xanthines reveal determinants of selectivity. Structure 25:1275–1285

    Article  PubMed  CAS  Google Scholar 

  • Childers SR, Li X, Xiao R et al (2005) Allosteric modulation of adenosine A1 receptor coupling to G-proteins in brain. J Neurochem 93(3):715–723

    Article  PubMed  CAS  Google Scholar 

  • Corino VD, Holmqvist F, Mainardi LT et al (2014) Beta-blockade and A1-adenosine receptor agonist effects on atrial fibrillatory rate and atrioventricular conduction in patients with atrial fibrillation. Europace 16(4):587–594

    Article  PubMed  Google Scholar 

  • Daly JW, Padgett W, Thompson RD et al (1986) Structure-activity relationships for N6-substituted adenosines at a brain A1-adenosine receptor with a comparison to an A2-adenosine receptor regulating coronary blood flow. Biochem Pharmacol 35:2467–2481

    Article  PubMed  CAS  Google Scholar 

  • Daly JW, Hong O, Padgett WL et al (1988) Non-xanthine heterocycles: activity as antagonists of A1- and A2-adenosine receptors. Biochem Pharmacol 37:655–664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dhalla AK, Santikul M, Smith M et al (2007) Antilipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: comparison with nicotinic acid. J Pharmacol Exp Ther 321(1):327–333

    Article  PubMed  CAS  Google Scholar 

  • Dhalla AK, Chisholm JW, Reaven GM et al (2009) A1 adenosine receptor: role in diabetes and obesity. Handb Exp Pharmacol 193:271–295

    Article  CAS  Google Scholar 

  • Dinh W, Albrecht-Küpper B, Gheorghiade M et al (2017) Partial adenosine A1 agonist in heart failure. Handb Exp Pharmacol 243:177–203

    Article  PubMed  Google Scholar 

  • Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, Freeman TC (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118:1461–1468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Drury AN, Szent-Györgyi A (1929) The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 68:213–237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elmenhorst D, Meyer PT, Matusch A et al (2012) Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET. J Nucl Med 53(11):1723–1729

    Article  PubMed  CAS  Google Scholar 

  • Elmenhorst D, Elmenhorst EM, Hennecke E et al (2017) Recovery sleep after extended wakefulness restores elevated A1 adenosine receptor availability in the human brain. PNAS 114(16):4243–4248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elzein E, Zablocki J (2008) A1 adenosine receptor agonists and their potential therapeutic applications. Expert Opin Investig Drugs 17(12):1901–1910

    Article  PubMed  CAS  Google Scholar 

  • Elzein E, Kalla R, Li XF et al (2007) N6-Cycloalkyl-2-substituted adenosine derivatives as selective, high affinity adenosine A1 receptor agonists. Bioorg Med Chem Lett 17:161–166

    Article  PubMed  CAS  Google Scholar 

  • Fedele DE, Li T, Lan JQ et al (2006) Adenosine A1 receptors are crucial in keeping an epileptic focus localized. Exp Neurol 200(1):184–190

    Article  PubMed  CAS  Google Scholar 

  • Ferrante A, Martire A, Pepponi R et al (2014) Expression, pharmacology and functional activity of adenosine A1 receptors in genetic models of Huntington’s disease. Neurobiol Dis 71:193–204

    Google Scholar 

  • Franchetti P, Cappellacci L, Vita P et al (2009) N6-Cycloalkyl- and N6-bicycloalkyl-C5′(C2′)-modified adenosine derivatives as high-affinity and selective agonists at the human A1 adenosine receptor with antinociceptive effects in mice. J Med Chem 52:2393–2406

    Article  PubMed  CAS  Google Scholar 

  • Fredholm BB (2011) Notes on the history of caffeine use. Handb Exp Pharmacol 200:1–9

    Article  CAS  Google Scholar 

  • Fredholm BB, IJzerman AP, Jacobson KA et al (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    PubMed  CAS  Google Scholar 

  • Fredholm BB, Johansson S, Wang YQ (2011) Adenosine and the regulation of metabolism and body temperature. Adv Pharmacol 61:77–94

    Article  PubMed  CAS  Google Scholar 

  • Fujita T, Feng C, Takano T (2017) Presence of caffeine reversibly interferes with efficacy of acupuncture-induced analgesia. Sci Rep 7(1):3397

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao ZG, Jacobson KA (2007) Emerging adenosine receptor agonists. Expert Opin Emerg Drugs 12(3):479–492

    Article  PubMed  CAS  Google Scholar 

  • Gao ZG, Jacobson KA (2017) Purinergic signaling in mast cell degranulation and asthma. Front Pharmacol 8:947

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao ZG, Melman N, Erdmann A et al (2003a) Differential allosteric modulation by amiloride analogues of agonist and antagonist binding at A1 and A3 adenosine receptors. Biochem Pharmacol 65(4):525–534

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gao ZG, Blaustein J, Gross AS et al (2003b) N6-substituted adenosine derivatives: selectivity, efficacy, and species differences at A3 adenosine receptors. Biochem Pharmacol 65:1675–1684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gao ZG, Kim SK, IJzerman AP et al (2005) Allosteric modulation of the adenosine family of receptor. Mini Rev Med Chem 5:545–553

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Garritsen A, IJzerman AP, Beukers MW et al (1990) Interaction of amiloride and its analogues with adenosine A1 receptors in calf brain. Biochem Pharmacol 40(4):827–834

    Article  PubMed  CAS  Google Scholar 

  • Giorgi I, Nieri P (2013) Adenosine A1 modulators: a patent update (2008 to present). Expert Opin Ther Pat 23(9):1109–1121

    Article  PubMed  CAS  Google Scholar 

  • Giorgi I, Leonardi M, Pietra D et al (2009) Synthesis, biological assays and QSAR studies of N-(9-benzyl-2-phenyl-8-azapurin-6-yl)-amides as ligands for A1 adenosine receptors. Bioorg Med Chem 17:1817–1830

    Article  PubMed  CAS  Google Scholar 

  • Glatter KA, Cheng J, Dorostkar P (1999) Electrophysiologic effects of adenosine in patients with supraventricular tachycardia. Circulation 99:1034–1040

    Article  PubMed  CAS  Google Scholar 

  • Glukhova A, Thal DM, Nguyen AT et al (2017) Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168(5):867–877

    Article  PubMed  CAS  Google Scholar 

  • Goldman N, Chen M, Fujita T et al (2010) Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci 13(7):883–888

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goodman RR, Cooper MJ, Gavish M et al (1982) Guanine nucleotide and cation regulation of the binding of [3H]cyclohexyladenosine and [3H]diethylphenylxanthine to adenosine A1 receptors in brain membranes. Mol Pharmacol 21(2):329–235

    PubMed  CAS  Google Scholar 

  • Gottlieb SS, Brater DC, Thomas I et al (2002) BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 10511:1348–1353

    Article  CAS  Google Scholar 

  • Gottlieb SS, Ticho B, Deykin A et al (2011) Effects of BG9928, an adenosine A1 receptor antagonist, in patients with congestive heart failure. J Clin Pharmacol 51(6):899–907

    Article  PubMed  CAS  Google Scholar 

  • Grahner B, Winiwarter S, Lanzner W et al (1994) Synthesis and structure-activity relationships of Deazaxanthines: analogs of potent AI- and at-adenosine receptor antagonists. J Med Chem 37:1526–1534

    Article  PubMed  CAS  Google Scholar 

  • Greene SJ, Sabbah HN, Butler J et al (2016) Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure. Heart Fail Rev 21(1):95–102

    Article  PubMed  CAS  Google Scholar 

  • Gütschow M, Schlenk M, Gäb J et al (2012) Benzothiazinones: a novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives. Med Chem 55(7):3331–3341

    Article  CAS  Google Scholar 

  • Hayashi S, Inaji M, Nariai T et al (2018) Increased binding potential of brain adenosine A1 receptor in chronic stages of patients with diffuse axonal injury measured with [1-methyl-11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine positron emission tomography imaging. J Neurotrauma 35:25–31

    Google Scholar 

  • Hill SJ (2006) G-protein-coupled receptors: past, present and future. Br J Pharmacol 147(Suppl 1):S27–S37

    PubMed  PubMed Central  CAS  Google Scholar 

  • Hocher B (2010) Adenosine A1 receptor antagonists in clinical research and development. Kidney Int 78(5):438–445

    Article  PubMed  CAS  Google Scholar 

  • Hua X, Erikson CJ, Chason KD et al (2007) Involvement of A1 adenosine receptors and neural pathways in adenosine-induced bronchoconstriction in mice. Am J Physiol Lung Cell Mol Physiol 293:L25–L32

    Article  PubMed  CAS  Google Scholar 

  • Huang M, Shimizu H, Daly JW (1972) Accumulation of cyclic adenosine monophosphate in incubated slices of brain tissue. 2. Effects of depolarizing agents, membrane stabilizers, phosphodiesterase inhibitors and adenosine analogs. J Med Chem 15:462–466

    Article  PubMed  CAS  Google Scholar 

  • Hunter CJ, Bennet L, Power GG et al (2003) Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep. Stroke 34(9):2240–2245

    Article  PubMed  CAS  Google Scholar 

  • IJzerman AP, van Galen PJ, Jacobson KA (1992) Molecular modeling of adenosine receptors. I. The ligand binding site on the A1 receptor. Drug Des Discov 9(1):49–67

    PubMed  PubMed Central  CAS  Google Scholar 

  • Ishiwata K, Kimura Y, de Vries EF et al (2007) PET tracers for mapping adenosine receptors as probes for diagnosis of CNS disorders. Cent Nerv Syst Agents Med Chem 7:57–77

    Article  CAS  Google Scholar 

  • Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nature Rev Drug Disc 5:247–264

    Article  CAS  Google Scholar 

  • Jacobson KA, Knutsen LJS (2001) P1 and P2 purine and pyrimidine receptors. In: Abbracchio MP, Williams M (eds) Handbook of experimental pharmacology, 151/I: purinergic and pyrimidinergic signalling I. Springer, Berlin, pp 129–175

    Chapter  Google Scholar 

  • Jacobson KA, Kirk KL, Padgett W et al (1985) Probing the adenosine receptor with adenosine and xanthine biotin conjugates. FEBS Lett 184:30–35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Ukena D, Kirk KL et al (1986) [3H]Xanthine amine congener of 1,3-dipropyl-8-phenylxanthine: an antagonist radioligand for adenosine receptors. Proc Natl Acad Sci U S A 83:4089–4093

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Ukena D, Padgett W et al (1987) Molecular probes for extracellular adenosine receptors. Biochem Pharmacol 36:1697–1707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Barone S, Kammula U et al (1989) Electrophilic derivatives of purines as irreversible inhibitors of A1-adenosine receptors. J Med Chem 32:1043–1051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Ji X-d, Li AH (2000) Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem 43:2196–2203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jacobson KA, Moro S, Manthey JA et al (2002) Interaction of flavones and other phytochemicals with adenosine receptors. In: Buslig B, Manthey J (eds) Flavonoids in cell function, Adv Exp Med Biol 505. Kluwer Academic/Plenum, New York, pp 163–171

    Google Scholar 

  • Jacobson KA, Gao ZG, Tchilibon S et al (2005) Semirational design of (N)-methanocarba nucleosides as dual acting A1 and A3 adenosine receptor agonists: novel prototypes for cardioprotection. J Med Chem 48:8103–8107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jespers W, Schiedel AC, Heitman LH et al (2018) Structural mapping of adenosine receptor Mutations: ligand binding and signaling mechanisms. Trends Pharmacol Sci 39(1):75–89

    Google Scholar 

  • Ji XD, Melman N, Jacobson KA (1996) Interactions of flavonoids and other phytochemicals with adenosine receptors. J Med Chem 39(3):781–788

    Article  PubMed  CAS  Google Scholar 

  • Johansson SM, Salehi A, Sandstrom ME et al (2007) A1 receptor deficiency causes increased insulin and glucagon secretion in mice. Biochem Pharmacol 74:1628–1635

    Article  PubMed  CAS  Google Scholar 

  • Jörg M, Glukhova A, Abdul-Ridha A et al (2016) Novel irreversible agonists acting at the A1 adenosine receptor. J Med Chem 59:11182–11194

    Article  PubMed  CAS  Google Scholar 

  • Kalk P, Eggert B, Relle K et al (2007) The adenosine A1 receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure. Br J Pharmacol 151:1025–1032

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Katritch V, Jaakola VP, Lane JR et al (2010) Structure-based discovery of novel Chemotypes for adenosine A2A receptor antagonists. J Med Chem 53:1799–1809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kennedy DP, McRobb FM, Leonhardt SA et al (2014) The second extracellular loop of the adenosine A1 receptor mediates activity of allosteric enhancers. Mol Pharmacol 85:301–309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kiesman WF, Zhao J, Conlon PR et al (2006a) Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists. J Med Chem 49:7119–7131

    Article  PubMed  CAS  Google Scholar 

  • Kiesman WF, Zhao J, Conlon PR et al (2006b) Norbornyllactone-substituted xanthines as adenosine A1 receptor antagonists. Bioorg Med Chem 14:3654–3661

    Article  PubMed  CAS  Google Scholar 

  • Kiesman WF, Elzein E, Zablocki J (2009) A1 adenosine receptor antagonists, agonists, and allosteric enhancers. Handb Exp Pharmacol 193:25–58

    Article  CAS  Google Scholar 

  • Kim YH, Nachman RJ, Pavelka L et al (1981) Doridosine, 1-methylisoguanosine, from Anisodoris nobilis; structure, pharmacological properties and synthesis. J Nat Prod 44:206–214

    Article  PubMed  CAS  Google Scholar 

  • Klaft ZJ, Hollnagel JO, Salar S et al (2016) Adenosine A1 receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices. Epilepsia 57:746–756

    Article  PubMed  CAS  Google Scholar 

  • Klotz KN, Hessling J, Hegler J et al (1998) Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells. Naunyn Schmiedeberg’s Arch Pharmacol 357:1–9

    Google Scholar 

  • Knight A, Hemmings JL, Winfield I et al (2016) Discovery of novel adenosine receptor agonists that exhibit subtype selectivity. J Med Chem 59:947–964

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi H, Ujike H, Iwata N et al (2011) Association analysis of the adenosine A1 receptor gene polymorphisms in patients with methamphetamine dependence/psychosis. Curr Neuropharmacol 9:137–142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kolb P, Phan K, Gao ZG et al (2012) Limits of ligand selectivity from docking to models: in silico screening for A1 adenosine receptor antagonists. PLoS One 7:e49910

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koul S, Ramdas V, Barawkar DA et al (2017) Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation. Bioorg Med Chem 25:1963–1975

    Article  PubMed  CAS  Google Scholar 

  • Kuroda S, Akahane A, Itani H et al (2000) Novel adenosine A1 receptor antagonists. Synthesis and structure-activity relationships of a novel series of 3-(2-Cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridines. Bioorg Med Chem 8:55–64

    Article  PubMed  CAS  Google Scholar 

  • Lane JR, Klaasse E, Lin J et al (2010) Characterization of [3H]LUF5834: a novel non-ribose high-affinity agonist radioligand for the adenosine A1 receptor. Biochem Pharmacol 80:1180–1189

    Article  PubMed  CAS  Google Scholar 

  • Langemeijer EV, Verzijl D, Dekker SJ et al (2013) Functional selectivity of adenosine A1 receptor ligands? Purinergic Signal 9:91–100

    Article  PubMed  CAS  Google Scholar 

  • Lee HE, Jeon SJ, Ryu B et al (2016) Swertisin, a C-glucosylflavone, ameliorates scopolamine-induced memory impairment in mice with its adenosine A1 receptor antagonistic property. Behav Brain Res 306:137–145

    Article  PubMed  CAS  Google Scholar 

  • Lehel SZ, Horvath G, Boros I et al (2000) Synthesis of 5’-N-(2-[18F]fluoroethyl)-carboxamidoadenosine: a promising tracer for investigation of adenosine receptor system by PET technique. J Label Compd Radiopharm 43:807–815

    Article  CAS  Google Scholar 

  • Li X, Conklin D, Pan HL et al (2003) Allosteric adenosine receptor modulation reduces hypersensitivity following peripheral inflammation by a central mechanism. J Pharmacol Exp Ther 305:950–955

    Article  PubMed  CAS  Google Scholar 

  • Li X, Conklin D, Ma W et al (2004) Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain. Anesthesiology 100:956–961

    Article  PubMed  CAS  Google Scholar 

  • Liao HY, Hsieh CL, Huang CP et al (2017) Electroacupuncture attenuates CFA-induced inflammatory pain by suppressing Nav1.8 through S100B, TRPV1, opioid, and adenosine pathways in mice. Sci Rep 7:42531

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Libert F, Van Sande J, Lefort A, Czernilofsky A, Dumont JE, Vassart G, Ensinger HA, Mendla KD (1992) Cloning and functional characterization of a human A1 adenosine receptor. Biochem Biophys Res Commun 187:919–926

    Article  PubMed  CAS  Google Scholar 

  • Liu DZ, Xie KQ, Ji XQ et al (2005) Neuroprotective effect of paeoniflorin on cerebral ischemic rat by activating adenosine A1 receptor in a manner different from its classical agonists. Br J Pharmacol 146:604–611

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu DZ, Zhao FL, Liu J et al (2006) Potentiation of adenosine A1 receptor agonist CPA-induced antinociception by paeoniflorin in mice. Biol Pharm Bull 29:1630–1633

    Article  PubMed  CAS  Google Scholar 

  • Lohse MJ, Klotz KN, Diekmann E et al (1988) 2’,3’-Dideoxy-N6-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors. Eur J Pharmacol 156:157–160

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Louvel J, Guo D, Agliardi M, Mocking TAM et al (2014) Agonists for the adenosine A1 receptor with tunable residence time. A case for non-ribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines. J Med Chem 57:3213–3222

    Article  PubMed  CAS  Google Scholar 

  • Louvel J, Guo D, Soethoudt M et al (2015) Structure-kinetics relationships of Capadenoson derivatives as adenosine A1 receptor agonists. Eur J Med Chem 101:681–691

    Article  PubMed  CAS  Google Scholar 

  • Luongo L, Petrelli R, Gatta L et al (2012) 5′-Chloro-5′-deoxy-ENBA, a potent and selective adenosine A1 receptor agonist, alleviates neuropathic pain in mice through functional glial and microglial changes without affecting motor and cardiovascular functions. Molecules 17:13712–13726

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lynge J, Hellsten Y (2000) Distribution of adenosine A1, A2A and A2B receptors in human skeletal muscle. Acta Physiol Scand 169:283–290

    Article  PubMed  CAS  Google Scholar 

  • Maemoto T, Tada M, Mihara T et al (2004) Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors. J Pharmacol Sci 96:42–52

    Article  PubMed  CAS  Google Scholar 

  • Mahan LC, McVittie LD, Smyk-Randall EM et al (1991) Cloning and expression of an A1 adenosine receptor from rat brain. Mol Pharmacol 40:1–7

    PubMed  CAS  Google Scholar 

  • Mason PK, DiMarco JP (2009) New pharmacological agents for arrhythmias. Circ Arrhythm Electrophysiol 2:588–597

    Article  PubMed  CAS  Google Scholar 

  • Massie BM, O’Connor CM, Metra M, PROTECT Investigators and Committees Collaborators et al (2010) Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 363:1419–1428

    Article  PubMed  Google Scholar 

  • Matsuya T, Takamatsu H, Murakami Y et al (2005) Synthesis and evaluation of [11C]FR194921 as a nonxanthine-type PET tracer for adenosine A1 receptors in the brain. Nucl Med Biol 32:837–844

    Article  PubMed  CAS  Google Scholar 

  • McNamara N, Gallup M, Khong A, Sucher A, Maltseva I, Fahy J, Basbaum C (2004) Adenosine up-regulation of the mucin gene, MUC2, in asthma. FASEB J 18:1770–1772

    Article  PubMed  CAS  Google Scholar 

  • Meibom D, Albrecht-Küpper B, Diedrichs N et al (2017) Neladenoson Bialanate hydrochloride: a Prodrug of a partial adenosine A1 receptor agonist for the chronic treatment of heart diseases. Chem Med Chem 12:728–737

    Article  PubMed  CAS  Google Scholar 

  • Mendiola-Precoma J, Padilla K, Rodríguez-Cruz A et al (2017) Theobromine-induced changes in A1 Purinergic receptor gene expression and distribution in a rat brain Alzheimer’s disease model. J Alzheimers Dis 55:1273–1283

    Article  PubMed  CAS  Google Scholar 

  • Merskey H, Hamilton JT (1989) An open label trial of the possible analgesic effects of dipyridamole. J Pain Symptom Manag 4(1):34–37

    Article  CAS  Google Scholar 

  • Middleton RJ, Briddon SJ, Cordeaux Y et al (2007) New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells. J Med Chem 50:782–793

    Article  PubMed  CAS  Google Scholar 

  • Mitani T, Watanabe S, Yoshioka Y et al (2017) Theobromine suppresses adipogenesis through enhancement of CCAAT-enhancer-binding protein β degradation by adenosine receptor A1. Biochim Biophys Acta 1864:2438–2448

    Article  CAS  Google Scholar 

  • Moro S, Gao ZG, Jacobson KA et al (2006) Progress in pursuit of therapeutic adenosine receptor antagonists. Med Res Rev 26:131–159

    Article  PubMed  CAS  Google Scholar 

  • Müller CE (1997) A1-adenosine receptor antagonists. Expert Opin Ther Pat 7(5):419–440

    Article  Google Scholar 

  • Müller CE, Jacobson KA (2011) Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta Biomembr 1808:1290–1308

    Article  CAS  Google Scholar 

  • Myers J, Sall K, DuBiner H et al (2013) A Randomized, Phase II Study of Trabodenoson (INO-8875) in Adults with Ocular Hypertension (OHT) or Primary Open-Angle Glaucoma (POAG). Invest Ophthalmol Vis Sci 54:2621

    Google Scholar 

  • Nair V, Fasbender AJ (1991) High selectivity of novel isoguanosine analogs for the adenosine A1 receptor. Bioorg Med Chem Lett 1:481–486

    Article  CAS  Google Scholar 

  • Narlawar R, Lane JR, Doddareddy M et al (2010) Hybrid ortho/allosteric ligands for the adenosine A1 receptor. J Med Chem 53:3028–3037

    Article  PubMed  CAS  Google Scholar 

  • Nguyen AT, Baltos JA, Thomas T et al (2016a) Extracellular loop 2 of the adenosine A1 receptor has a key role in Orthosteric ligand affinity and agonist efficacy. Mol Pharmacol 90(6):703–714

    Article  PubMed  CAS  Google Scholar 

  • Nguyen AT, Vecchio EA, Thomas T et al (2016b) Role of the second extracellular loop of the adenosine A1 receptor on allosteric modulator binding, signaling, and Cooperativity. Mol Pharmacol 0(6):715–725

    Article  CAS  Google Scholar 

  • Obata H, Li X, Eisenach JC (2004) Spinal adenosine receptor activation reduces hypersensitivity after surgery by a different mechanism than after nerve injury. Anesthesiology 100:1258–1262

    Article  PubMed  CAS  Google Scholar 

  • Olah ME, Ren H, Ostrowski J et al (1992) Cloning, expression, and characterization of the unique bovine A1-adenosine receptor: Studies on the ligand binding site by site directed mutagenesis. J Biol Chem 267:10764–10770

    PubMed  CAS  Google Scholar 

  • Olah ME, Jacobson KA, Stiles GL (1994) Role of the second extracellular loop of adenosine receptors in agonist and antagonist binding: analysis of chimeric A1/A3 adenosine receptors. J Biol Chem 269:24692–24698

    PubMed  CAS  Google Scholar 

  • Osswald H, Schnermann J (2011) Methylxanthines and the kidney. Handb Exp Pharmacol 200:391–412

    Article  CAS  Google Scholar 

  • Pan HL, Xu Z, Leung E et al (2001) Allosteric adenosine modulation to reduce allodynia. Anesthesiology 95:416–420

    Article  PubMed  CAS  Google Scholar 

  • Paul S, Elsinga PH, Ishiwata K, Dierckx RA, van Waarde A (2011) Adenosine A1 receptors in the central nervous system: their functions in health and disease, and possible elucidation by PET imaging. Curr Med Chem 18:4820–4835

    Article  PubMed  CAS  Google Scholar 

  • Peeters MC, Wisse LE, Dinaj A et al (2012) The role of the second and third extracellular loops of the adenosine A1 receptor in activation and allosteric modulation. Biochem Pharmacol 84(1):76–87

    Article  PubMed  CAS  Google Scholar 

  • Peleli M, Carlstrom M (2017) Adenosine signaling in diabetes mellitus and associated cardiovascular and renal complications. Mol Asp Med 55:62–74

    Article  CAS  Google Scholar 

  • Pelleg A, Kutalek SP, Flammang D et al (2012) ATPace™: injectable adenosine 5’-triphosphate: Diagnostic and therapeutic indications. Purinergic Signal 8(Suppl 1):57–60

    Article  PubMed  CAS  Google Scholar 

  • Peng Z, Borea PA, Varani K et al (2009) Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest 119(3):582–594

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Petrelli R, Scortichini M, Kachler S et al (2017) Exploring the role of N6-substituents in potent dual acting 5’-C-ethyl-tetrazolyl-adenosine derivatives: synthesis, binding, functional assays and antinociceptive effects in mice. J Med Chem 60:4327–4341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Picano E, Michelassi C (1997) Chronic oral dipyridamole as a ‘novel’ antianginal drug: the collateral hypothesis. Cardiovasc Res 33(3):666–670

    Article  PubMed  CAS  Google Scholar 

  • Ponnoth DS, Nadeem A, Tilley S et al (2010) Involvement of A1 adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma. Am J Physiol Heart Circ Physiol 299:H81–H87

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reppert SM, Weaver DR, Stehle JH et al (1991) Molecular cloning and characterization of a rat A1-adenosine receptor that is widely expressed in brain and spinal cord. Mol Endocrinol 5(8):1037–1048

    Article  PubMed  CAS  Google Scholar 

  • Rittiner JE, Korboukh I, Hull-Ryde EA et al (2012) AMP is an adenosine A1 receptor agonist. J Biol Chem 287(8):5301–5309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rivkees SA, Lasbury ME, Barbhaiya H (1995) Identification of domains of the human A1 adenosine receptor that are important for binding receptor subtype-selective ligands using chimeric A1/A2a adenosine receptors. J Biol Chem 270(35):20485–20490

    Article  PubMed  CAS  Google Scholar 

  • Rivkees SA, Barbhaiya H, IJzerman AP (1999) Identification of the adenine binding site of the human A1 adenosine receptor. J Biol Chem 274(6):3617–3621

    Article  PubMed  CAS  Google Scholar 

  • Robeva AS, Woodard RL, Jin X, Cao Z, Bhattacharya S, Taylor HE, Rosin DL, Linden J (1996) Molecular characterization of recombinant human adenosine receptors. Drug Dev Res 39:243–252

    Article  CAS  Google Scholar 

  • Rodríguez D, Gao ZG, Moss SM et al (2015) Molecular docking screening using agonist-bound GPCR structures: probing the A2A adenosine receptor. J Chem Inf Model 55:550–563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rodríguez D, Chakraborty S, Warnick E et al (2016) Structure-based screening of uncharted chemical space for atypical adenosine receptor agonists. ACS Chem Biol 11:2763–2772

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Roelen H, Veldman N, Spek AL et al (1996) N6,C8-Disubstituted adenosine derivatives as partial agonists for adenosine A1 receptors. J Med Chem 39(7):1463–1471

    Article  PubMed  CAS  Google Scholar 

  • Romagnoli R, Baraldi PG, Moorman AR et al (2015) Current status of A1 adenosine receptor allosteric enhancers. Future Med Chem 7:1247–1259

    Article  PubMed  CAS  Google Scholar 

  • Rosentreter U, Kramer T, Vaupel A et al (2004) Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines with adenosine receptor-binding activity and their use cardiovascular preparations. US 2004/0102626 A1

    Google Scholar 

  • Sattin A, Rall TW (1970) The effect of adenosine and adenine nucleotides on the cyclic adenosine 3’,5’-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol 6:13–23

    PubMed  CAS  Google Scholar 

  • Sawynok J (2016) Adenosine receptor targets for pain. Neuroscience 338:1–18

    Article  PubMed  CAS  Google Scholar 

  • Schaddelee MP, Read KD, Cleypool CG et al (2005) Brain penetration of synthetic adenosine A1 receptor agonists in situ: role of the rENT1 nucleoside transporter and binding to blood constituents. Eur J Pharm Sci 24:59–66

    Article  PubMed  CAS  Google Scholar 

  • Scheiff A, Yerande SG, El-Tayeb A et al (2010) 2-Amino-5-benzoyl-4-phenylthiazoles: development of potent and selective adenosine A1 receptor antagonists. Bioorg Med Chem 18:2195–2203

    Article  PubMed  CAS  Google Scholar 

  • Schenone S, Brullo C, Musumeci F et al (2010) A1 receptors ligands: past, present and future trends. Curr Top Med Chem 10:878–890

    Article  PubMed  CAS  Google Scholar 

  • Schnackenberg CG, Merz E, Brooks DP (2003) An orally active adenosine A1 receptor antagonist, FK838, increases renal excretion and maintains glomerular filtration rate in furosemide-resistant rats. Br J Pharmacol 139(8):1383–1388

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Serchov T, Clement HW, Schwartz MK et al (2015) Increased signaling via adenosine A1 receptors, sleep deprivation, imipramine, and ketamine inhibit depressive-like behavior via induction of Homer1a. Neuron 87:549–562

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shamim MT, Ukena D, Padgett WL et al (1988) 8-Aryl-and 8-cycloalkyl-1,3-dipropylxanthines: further potent and selective antagonists for A1-adenosine receptors. J Med Chem 31(3):613–617

    Article  PubMed  CAS  Google Scholar 

  • Siddiqi SM, Ji XD, Melman N et al (1996) A survey of non-xanthine derivatives as adenosine receptor ligands. Nucleosides Nucleotides Nucleic Acids 15:693–718

    Article  CAS  Google Scholar 

  • Staehr PM, Dhalla AK, Zack J et al (2013) Reduction of free fatty acids, safety, and pharmacokinetics of oral GS-9667, an A1 adenosine receptor partial agonist. J Clin Pharmacol 53(4):385–392

    Article  PubMed  Google Scholar 

  • Stein MB, Black B, Brown TM et al (1993) Lack of efficacy of the adenosine reuptake inhibitor dipyridamole in the treatment of anxiety disorders. Biol Psychiatry 33(8–9):647–650

    Article  PubMed  CAS  Google Scholar 

  • Stiles GL, Jacobson KA (1988) High affinity acylating antagonists for the A1 adenosine receptor: identification of binding subunit. Mol Pharmacol 34:724–728

    PubMed  CAS  Google Scholar 

  • Stockwell J, Jakova E, Cayabyab FS (2017) Adenosine A1 and A2A receptors in the brain: current research and their role in neurodegeneration. Molecules 22(4):E676

    Google Scholar 

  • Suzuki F, Shimada J, Mizumoto H, Karasawa A, Kubo K, Nonaka H, Ishii A, Kawakita T (1992) Adenosine A1 antagonists. 2. Structure–activity relationships on diuretic activities and protective effects against acute renal failure. J Med Chem 35:3066–3075

    Article  PubMed  CAS  Google Scholar 

  • Szentmiklósi AJ, Cseppento A, Harmati G et al (2011) Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs. Curr Med Chem 18(8):1164–1187

    Article  PubMed  Google Scholar 

  • Szentmiklósi AJ, Galajda Z, Cseppento Á et al (2015) The Janus face of adenosine: antiarrhythmic and proarrhythmic actions. Curr Pharm Des 21(8):965–976

    Article  PubMed  CAS  Google Scholar 

  • Tang LM, Liu IM, Cheng JT (2003) Stimulatory effect of paeoniflorin on adenosine release to increase the glucose uptake into white adipocytes of Wistar rat. Planta Med 69(4):332–336

    Article  PubMed  CAS  Google Scholar 

  • Tao PL, Yen MH, Shyu WS et al (1993) Doridosine derivatives: binding at adenosine receptors and in vivo effects. Eur J Pharmacol 243(2):135–139

    Article  PubMed  CAS  Google Scholar 

  • Tendera M, Gaszewska-Żurek E, Parma Z et al (2012) The new oral adenosine A1 receptor agonist capadenoson in male patients with stable angina. Clin Res Cardiol 101(7):585–591

    Article  PubMed  CAS  Google Scholar 

  • Thompson RD, Secunda S, Daly JW et al (1991) N6,9-Disubstituted adenines: a potent, selective antagonists at the A1 adenosine receptor. J Med Chem 34:2877–2882

    Article  PubMed  CAS  Google Scholar 

  • Tosh DK, Phan K, Gao ZG et al (2012a) Optimization of adenosine 5’-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment-based searching. J Med Chem 55:4297–4308

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tosh DK, Paoletta S, Deflorian F et al (2012b) Structural sweet spot for A1 adenosine receptor activation by truncated (N)-methanocarba nucleosides: receptor docking and potent anticonvulsant activity. J Med Chem 55:8075–8090

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Townsend-Nicholson A, Schofield PR (1994) A threonine residue in the seventh transmembrane domain of the human A1 adenosine receptor mediates specific agonist binding. J Biol Chem 269(4):2373–2376

    PubMed  CAS  Google Scholar 

  • Trivedi BK, Bridges AJ, Patt WC et al (1989) N6-bicycloalkyl-adenosines with unusually high potency and selectivity for the adenosine A1 receptor. J Med Chem 32(1):8–11

    Article  PubMed  CAS  Google Scholar 

  • Tuomi T, Santoro N, Caprio S et al (2014) The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383(9922):1084–1094

    Article  PubMed  Google Scholar 

  • Ukena D, Jacobson KA, Kirk KL et al (1986) A [3H]amine congener of 1,3-dipropyl-8-phenylxanthine. A new radioligand for A2 adenosine receptors of human platelets. FEBS Lett 199:269–274

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Calker D, Muller M, Hamprecht B (1979) Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem 33:999–1005

    Article  PubMed  Google Scholar 

  • van der Klein PA, Kourounakis AP, IJzerman AP (1999) Allosteric modulation of the adenosine A1 receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding. J Med Chem 42(18):3629–3635

    Article  PubMed  CAS  Google Scholar 

  • van der Wenden EM, Carnielli M, Roelen HCPF et al (1998) 5’-substituted adenosine analogs as new high-affinity partial agonists for the adenosine A1 receptor. J Med Chem 41(1):102–110

    Article  PubMed  Google Scholar 

  • van Galen PJ, Leusen FJ, IJzerman AP et al (1989) Mapping the N6-region of the adenosine A1 receptor with computer graphics. Eur J Pharmacol 172(1):19–27

    Article  PubMed  Google Scholar 

  • van Galen PJ, van Vlijmen HW, IJzerman AP et al (1990) A model for the antagonist binding site on the adenosine A1 receptor, based on steric, electrostatic, and hydrophobic properties. J Med Chem 33(6):1708–1713

    Article  PubMed  Google Scholar 

  • van Galen PJM, Stiles GL, Michaels G et al (1992) Adenosine A1 and A2 receptors: structure-function relationships. Med Res Rev 12:423–471

    Article  PubMed  PubMed Central  Google Scholar 

  • van Galen PJM, van Bergen AH, Gallo-Rodriguez C et al (1994) A binding site model and structure-activity relationships for the rat A3 adenosine receptor. Mol Pharmacol 45:1101–1111

    PubMed  Google Scholar 

  • van Veldhoven JPD, Chang LCW, von Frijtag Drabbe Kunzel JK et al (2008) A new generation of adenosine receptor antagonists: from di- to trisubstituted aminopyrimidines. Bioorg Med Chem 16:2741–2752

    Article  PubMed  CAS  Google Scholar 

  • van Rhee AM, Siddiqi SM, Melman N et al (1996) Tetrahydrobenzothiophenone derivatives as a novel class of adenosine receptor antagonists. J Med Chem 39:398–406

    Article  PubMed  Google Scholar 

  • Varani K, Vincenzi F, Merighi S et al (2017) Biochemical and pharmacological role of A1 adenosine receptors and their modulation as novel therapeutic strategy. Adv Exp Med Biol Protein Rev 19:193–232

    Article  Google Scholar 

  • Verzijl D, IJzerman AP (2011) Functional selectivity of adenosine receptor ligands. Purinergic Signalling 7:171

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vincenzi F, Targa M, Romagnoli R et al (2014) TRR469, a potent A1 adenosine receptor allosteric modulator, exhibits antinociceptive properties in acute and neuropathic pain models in mice. Neuropharmacology 82:6–14

    Article  CAS  Google Scholar 

  • Vincenzi F, Ravani A, Pasquini S et al (2016) Positive allosteric modulation of A1 adenosine receptors as a novel and promising therapeutic strategy for anxiety. Neuropharmacology 111:283–292

    Article  PubMed  CAS  Google Scholar 

  • Vittori S, Lorenzen A, Stannek C et al (2000) N-Cycloalkyl derivatives of adenosine and 1-Deazaadenosine as agonists and partial agonists of the A1 adenosine receptor. J Med Chem 43(2):250–260

    Article  PubMed  CAS  Google Scholar 

  • Voors AA, Düngen HD, Senni M et al (2017) Safety and tolerability of Neladenoson Bialanate, a novel oral partial adenosine A1 receptor agonist, in patients with chronic heart failure. J Clin Pharmacol 57(4):440–451

    Article  PubMed  CAS  Google Scholar 

  • Wagner AK, Miller MA, Scanlon J et al (2010) Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI. Epilepsy Res 90(3):259–272

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weyler S, Fülle F, Diekmann M et al (2006) Improving potency, selectivity, and water solubility of adenosine A1 receptor antagonists: Xanthines modified at position 3 and related Pyrimido[1,2,3-cd]purinediones. J Med Chem 1:891–902

    CAS  Google Scholar 

  • Xie KQ, Cao Y, Zhu XZ (2006) Role of the second transmembrane domain of rat adenosine A1 receptor in ligand-receptor interaction. Biochem Pharmacol 71(6):865–871

    Article  PubMed  CAS  Google Scholar 

  • Xu B, Berkich DA, Crist GH et al (1998) A1 adenosine receptor antagonism improves glucose tolerance in Zucker rats. Am J Phys 274(2 Pt 1):E271–E279

    CAS  Google Scholar 

  • Yang T, Gao X, Sandberg M et al (2015) Abrogation of adenosine A1 receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses. Diabetologia 58(7):1610–1620

    Article  PubMed  CAS  Google Scholar 

  • Yen LT, Hsieh CL, Hsu HC et al (2017) Targeting ASIC3 for relieving mice fibromyalgia pain: roles of Electroacupuncture, opioid, and adenosine. Sci Rep 7:46663

    Article  PubMed  PubMed Central  Google Scholar 

  • Yin D, Liu YY, Wang TX et al (2016) Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model. Psychopharmacology 233(2):281–293

    Article  PubMed  CAS  Google Scholar 

  • Yuliana ND, Khatib A, Link-Struensee AM et al (2009) Adenosine A1 receptor binding activity of methoxy flavonoids from Orthosiphon stamineus. Planta Med 75(2):132–136

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Zhan-Guo Gao, Dilip K. Tosh & Shanu Jain

  2. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Jinha Yu, Rama R. Suresh & Kenneth A. Jacobson

Authors
  1. Zhan-Guo Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dilip K. Tosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shanu Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinha Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rama R. Suresh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenneth A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth A. Jacobson .

Editor information

Editors and Affiliations

  1. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Pier Andrea Borea

  2. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Katia Varani

  3. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Stefania Gessi

  4. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Stefania Merighi

  5. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Fabrizio Vincenzi

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gao, ZG., Tosh, D.K., Jain, S., Yu, J., Suresh, R.R., Jacobson, K.A. (2018). A1 Adenosine Receptor Agonists, Antagonists, and Allosteric Modulators. In: Borea, P., Varani, K., Gessi, S., Merighi, S., Vincenzi, F. (eds) The Adenosine Receptors. The Receptors, vol 34. Humana Press, Cham. https://doi.org/10.1007/978-3-319-90808-3_4

Download citation

Publish with us

Policies and ethics

Search

Navigation