Skip to main content
SpringerLink
Log in

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

  • Chapter
  • First Online:
Adenosine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 193))

Abstract

A3 adenosine receptor (A3AR) ligands have been modified to optimize their interaction with the A3AR. Most of these modifications have been made to the N6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A3AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A3AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A3AR antagonists. Probably due to the “enigmatic” physiological role of A3AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A3AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.

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 389.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 499.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 549.99
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

Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

AR:

Adenosine receptor

b:

Bovine

cAMP:

Cyclic adenosine monophosphate

CHO cells:

Chinese hamster ovary cells

Cl–IB–MECA:

2-Chloro-N 6-(3-iodobenzyl)-5′-N-methylcarboxamido- adenosine

CoMFA:

Comparative molecular field analysis

CVT-3146:

1-{9-[(4S, 2R, 3R, 5R)-3,4-Dihydroxy-5-(hydroxymethyl) oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- methylcarboxamide

DBXRM:

7-β-d-Ribofuronamide

DHP:

1,4-Dihydropyridine

Et:

Ethyl

GPCR:

G-protein-coupled receptor

h:

Human

HEK293 cells:

Human embryonic kidney 293 cells

I–AB–MECA:

N 6-(4-Amino-3-iodobenzyl)-5′-N-methylcabroxamidoa- denosine

IB–MECA:

N 6-(3-Iodobenzyl)-5′-N-methylcarboxamidoadenosine

KF-26777:

2-(4-Bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one

LJ-529:

2-Chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′- methyluronamide

LJ-1251:

(2R, 3R, 4S)-2-(2-Chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol

LJ-1416:

(2R, 3R, 4S)-2-(2-Chloro-6-(3-chlorobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol

LUF6000:

N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c] quinolin-4-amine

Me:

Methyl

MRE-3005-F20:

5-N-(4-Methoxyphenylcarbamoyl)amino-8-ethyl-2-(2-furyl) pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

MRE-3008-F20:

5-N-(4-Methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl) pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

MRS1191:

1,4-Dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3, 5-pyridinedicarboxylic acid, 3-ethyl 5-(phenylmethyl) ester

MRS1220:

N-[9-Chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-yl]benzeneacetamide

MRS1292:

(2R, 3R, 4S, 5S)-2-[N 6-3-Iodobenzyl)adenos-9′-yl]-7-aza-1-oxa-6-oxospiro[4.4]-nonan-4,5-diol

MRS1523:

5-Propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)- 6-phenylpyridine-5-carboxylate

MRS3558:

(1′ S, 2′ R, 3′ S, 4′ R, 5′ S)-4-{2-Chloro-6-[(3-iodophenylmethyl) amino]purin-9-yl}-1-(methylaminocarbonyl)bicyclo-[3.1.0]-hexane-2,3-diol

MRS3777:

2-(Phenyloxy)-N 6-cyclohexyladenine

MRS5127:

(1′ R, 2′ R, 3′ S, 4′ R, 5′ S)-4′-[2-chloro-6-(3-iodobenzylamino)-purine]-2′, 3′-O-dihydroxybicyclo-[3.1.0]hexane

MRS5147:

(1′ R, 2′ R, 3′ S, 4′ R, 5′ S)-4′-[2-chloro-6- (3-bromobenzylamino)-purine]-2′, 3′-O-dihydroxybicyclo- [3.1.0]hexane

MRS5151:

(1′ S, 2′ R, 3′ S, 4′ S, 5′ S)-4′-[6-(3-chlorobenzylamino)-2-(5-hydroxycarbonyl-1-pentynyl)-9-yl]-2′, 3′-dihydroxybicyclo[3.1.0]hexane-1′-carboxylic acid N-methylamide

NECA:

adenosine 5′-N-ethyluronamide

OT-7999:

5-n-Butyl-8-(4-trifluoromethylphenyl)-3H-[1,2,4]triazolo-[5,1-i]purine

Pr:

Propyl

PSB-10:

8-Ethyl-1,4,7,8-tetrahydro-4-methyl-2-(2,3,5-trichlorophenyl)-5H-imidazo[2,1-i]purin-5-one

PSB-11:

(R)-4-Methyl-8-ethyl-2-phenyl-4,5,7,8-tetrahydro-1H- imidazo[2,1-i]purin-5-one

QSAR:

Quantitative structure–activity relationships

r:

Rat

SARs:

Structure–activity relationships

TM:

Transmembrane domain

VUF 5574:

N-(2-Methoxyphenyl)-N ′-(2-(3-pyridyl)quinazolin-4-yl)urea

VUF 8504:

4-Methoxy-N-(3-(2-pyridinyl)-1-isoquinolinyl)benzamide

References

  • Baharav E, Bar-Yehuda S, Madi L, Silberman D, Rath-Wolfson L, Halpren M, Ochaion A, Weinberger A, Fishman P (2005) Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. J Rheumatol 32:469–476

    CAS  PubMed  Google Scholar 

  • Baraldi PG, Cacciari B, Pineda de las Infantas MJ, Romagnoli R, Spalluto G, Volpini R, Costanzi S, Vittori S, Cristalli G, Melman N, Park K-S, Ji X-d, Jacobson KA (1998) Synthesis and biological activity of a new series of N 6-arylcarbamoyl-, 2-(ar)alkynyl-N 6-arylcarbamoyl, and N 6-carboxamido- derivatives of adenosine-5′-N-ethyluronamide (NECA) as A1 and A3 adenosine receptor agonists. J Med Chem 41:3174–3185

    Google Scholar 

  • Baraldi PG, Cacciari B, Borea PA, Varani K, Pastorin G, Da Ros T, Spalluto G (2002a) Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor antagonists: a possible template for adenosine receptor subtypes? Curr Pharm Design 8:99–110

    Article  Google Scholar 

  • Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Monopoli A, Ongini E, Varani K, Borea PA (2002b) 7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility. J Med Chem 45:115–126

    Article  CAS  PubMed  Google Scholar 

  • Baraldi PG, Tabrizi MA, Fruttarolo F, Bovero A, Avitabile B, Preti D, Romagnoli R, Merighi S, Gessi S, Varani K, Borea PA (2003a) Recent developments in the field of A3 adenosine receptor antagonists. Drug Dev Res 58:315–329

    Article  CAS  Google Scholar 

  • Baraldi PG, Fruttarolo F, Tabrizi MA, Preti D, Romagnoli R, El-Kashef H, Moorman A, Varani K, Gessi S, Merighi S, Borea PA (2003b) Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists. J Med Chem 46:1229–1241

    Article  CAS  PubMed  Google Scholar 

  • Baraldi PG, Tabrizi MA, Preti D, Bovero A, Fruttarolo F, Romagnoli R, Zaid NA, Moorman AR, Varani K, Borea PA (2005a) New 2-arylpyrazolo[4,3-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists. J Med Chem 48:5001–5008

    Article  CAS  PubMed  Google Scholar 

  • Baraldi PG, Preti D, Tabrizi MA, Fruttarolo F, Romagnoli R, Zaid NA, Moorman AR, Merighi S, Varani K, Borea PA (2005b) New pyrrolo[2,1-f]purine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives as potent and selective human A3 adenosine receptor antagonists. J Med Chem 48:4697–4701

    Article  CAS  PubMed  Google Scholar 

  • Baraldi PG, Tabrizi MA, Romagnoli R, El-Kashef H, Preti D, Bovero A, Fruttarolo F, Gordaliza M, Borea PA (2006) Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine template: organic and medicinal chemistry approach. Curr Org Chem 10:259–275

    Article  CAS  Google Scholar 

  • Bhattacharya P, Leonard JT, Roy K (2005) Exploring QSAR of thiazole and thiadiazole derivatives as potent and selective human adenosine A3 receptor antagonists using FA and GFA techniques. Bioorg Med Chem 13:1159–1165

    Article  CAS  PubMed  Google Scholar 

  • Biagi G, Bianucci AM, Coi A, Costa B, Fabbrini L, Giorgi I, Livi O, Micco I, Pacchini F, Santini E, Leonardi M, Nofal FA, Salernid OL, Scartonia V (2005) 2,9-Disubstituted-N 6-(arylcarbamoyl)-8-azaadenines as new selective A3 adenosine receptor antagonists: synthesis, biochemical and molecular modelling studies. Bioorg Med Chem 13:4679–4693

    Article  CAS  PubMed  Google Scholar 

  • Cacciari B, Bolcato C, Spalluto G, Klotz KN, Bacilieri M, Deflorian F, Moro S (2007) Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: a complete structure–activity profile. Purinergic Signal 3:183–193

    Article  CAS  PubMed  Google Scholar 

  • Catarzi D, Colotta V, Varano F, Calabri FR, Lenzi O, Filacchioni G, Trincavelli L, Martini C, Tralli A, Christian M, Moro S (2005a) 2-Aryl-8-chloro-1,2,4-triazolo[1,5-a]quinoxalin-4-amines as highly potent A1 and A3 adenosine receptor antagonists. Bioorg Med Chem 13:705–715

    Article  CAS  PubMed  Google Scholar 

  • Catarzi D, Colotta V, Varano F, Lenzi O, Filacchioni G, Trincavelli L, Martini C, Montopoli C, Moro S (2005b) 1,2,4-Triazolo[1,5-a]quinoxaline as a versatile tool for the design of selective human A3 adenosine receptor antagonists: synthesis, biological evaluation, and molecular modeling studies of 2-(hetero)aryl- and 2-carboxy-substitued derivatives. J Med Chem 48:7932–7945

    Article  CAS  PubMed  Google Scholar 

  • Chang LC, von Frijtag Drabbe Künzel JK, Mulder-Krieger T, Spanjersberg RF, Roerink SF, van den Hout G, Beukers MW, Brussee J, IJzerman AP (2005) A series of ligands displaying a remarkable agonistic–antagonistic profile at the adenosine A1 receptor. J Med Chem 48: 2045–2053

    Article  CAS  PubMed  Google Scholar 

  • Colotta V, Catarzi D, Varano F, Cecchi L, Filacchioni G, Martini C, Trincavelli L, Lucacchini A (2000) Synthesis and structure–activity relationships of a new set of 2-arylpyrazolo [3,4-c]quinoline derivatives as adenosine receptor antagonists. J Med Chem 43:3118–3124

    Article  CAS  PubMed  Google Scholar 

  • Colotta V, Catarzi D, Varano F, Calabri FR, Lenzi O, Filacchioni G, Martini C, Trincavelli L, Deflorian F, Moro S (2004) 1,2,4-Triazolo[4,3-a]quinoxalin-1-one moiety as an attractive scaffold to develop new potent and selective human A3 adenosine receptor antagonists: synthesis, pharmacological, and ligand–receptor modeling studies. J Med Chem 47:3580–3590

    Article  CAS  PubMed  Google Scholar 

  • Colotta V, Catarzi D, Varano F, Capelli F, Lenzi O, Filacchioni G, Martini C, Trincavelli L, Ciampi O, Pugliese AM, Pedata F, Schiesaro A, Morizzo E, Moro S (2007) New 2-arylpyrazolo[3,4-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand–receptor modeling studies. J Med Chem 50:4061–4074

    Article  CAS  PubMed  Google Scholar 

  • Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ (2008) Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells. FASEB J 22:850–860

    Article  CAS  PubMed  Google Scholar 

  • Costanzi S, Tikhonova IG, Harden TK, Jacobson KA (2008) Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands. J Comput Aided Mol Des doi:10.1007/s10822-008-9218-3

    PubMed  Google Scholar 

  • Cosyn L, Gao ZG, Van Rompaey P, Lu C, Jacobson KA, Van Calenbergh S (2006a) Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands. Bioorg Med Chem 14:1403–1412

    Article  CAS  PubMed  Google Scholar 

  • Cosyn L, Palaniappan KK, Kim SK, Duong HT, Gao ZG, Jacobson KA, Van Calenbergh S (2006b) 2-Triazole-substituted adenosines: a new class of selective A3 adenosine receptor agonists, partial agonists, and antagonists. J Med Chem 49:7373–7383

    Article  CAS  PubMed  Google Scholar 

  • Da Settimo F, Primofiore G, Taliani S, Marini AM, La Motta C, Simorini F, Salerno S, Sergianni V, Tuccinardi T, Martinelli A, Cosimelli B, Greco G, Novellino E, Ciampi O, Trincavalle ML, Martini C (2007) 5-Amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: a versatile scaffold to obtain potent and selective A3 adenosine receptor antagonists. J Med Chem 50:5676–5684

    Article  PubMed  CAS  Google Scholar 

  • DeNinno MP, Masamune H, Chenard LK, DiRico KJ, Eller C, Etienne JB, Tickner JE, Kennedy SP, Knight DR, Kong J, Oleynek JJ, Tracey WR, Hill RJ (2003) 3′-Aminoadenosine-5′-uronamides: discovery of the first highly selective agonist at the human adenosine A3 receptor. J Med Chem 46:353–355

    Article  CAS  PubMed  Google Scholar 

  • DeNinno MP, Masamune H, Chenard LK, DiRico KJ, Eller C, Etienne JB, Tickner JE, Kennedy SP, Knight DR, Kong J, Oleynek JJ, Tracey WR, Hill RJ (2006) The synthesis of highly potent, selective, and water-soluble agonists at the human adenosine A3 receptor. Bioorg Med Chem Lett 16:2525–2527

    Article  CAS  PubMed  Google Scholar 

  • Drabczyńska A, Schumacher B, Müller CE, Karolak-Wojciechowska J, Michalak B, Pȩkala E, Kieć-Kononowicz K (2003) Impact of the aryl substituent kind and distance from pyrimido[2,1-f]purindiones on the adenosine receptor selectivity and antagonistic properties. Eur J Med Chem 38:397–402

    Article  PubMed  CAS  Google Scholar 

  • Elzein E, Palle V, Wu Y, Maa T, Zeng D, Zablocki J (2004) 2-Pyrazolyl-N 6-substituted adenosine derivatives as high affinity and selective adenosine A3 receptor agonists. J Med Chem 47: 4766–4773

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • Gallo-Rodriguez C, Ji X-D, Melman N, Siegman BD, Sanders LH, Orlina J, Fischer B, Pu Q-L, Olah ME, van Galen PJM, Stiles GL, Jacobson KA (1994) Structure–activity relationships of N 6-benzyladenosine-5′-uronamides as A3-selective adenosine agonists. J Med Chem 37: 636–646

    Article  CAS  PubMed  Google Scholar 

  • Gao ZG, Kim SK, Biadatti T, Chen W, Lee K, Barak D, Kim SG, Johnson CR, Jacobson KA (2002) Structural determinants of A3 adenosine receptor activation: nucleoside ligands at the agonist/antagonist boundary. J Med Chem 45:4471–4484

    Article  CAS  PubMed  Google Scholar 

  • Gao ZG, Blaustein J, Gross AS, Melman N, Jacobson KA (2003) N 6-Substituted adenosine derivatives: selectivity, efficacy, and species differences at A3 adenosine receptors. Biochem Pharmacol 65: 1675–1684

    Article  CAS  PubMed  Google Scholar 

  • Gao ZG, Mamedova L, Chen P, Jacobson KA (2004) 2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors. Biochem Pharmacol 68: 1985–1993

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Gao ZG, Joshi BV, Klutz A, Kim SK, Lee HW, Kim HO, Jeong LS, Jacobson KA (2006a) Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5′-ribofuran-uronamide moiety. Bioorg Med Chem Lett 16:596–601

    Article  CAS  PubMed  Google Scholar 

  • Gao ZG, Duong HT, Sonina T, Lim SK, Van Rompaey P, Van Calenbergh S, Mamedova L, Kim HO, Kim MJ, Kim AY, Liang BT, Jeong LS, Jacobson KA (2006b) Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists. J Med Chem 49:2689–2702

    Article  CAS  PubMed  Google Scholar 

  • Gatta F, Del Giudice MR, Borioni A, Borea PA, Dionisotti S, Ongini E (1993) Synthesis of imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines and 1,2,4-triazolo[5,1-i]purines: new potent adenosine A2 receptor antagonists. Eur J Med Chem 28:569–576

    Article  CAS  Google Scholar 

  • Gessi S, Merighi S, Varani K, Leung E, Mac Lennan S, Borea PA (2008) The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 117:123–140

    Article  CAS  PubMed  Google Scholar 

  • Göblyös A, Gao ZG, Brussee J, Connestari R, Neves Santiago S, Ye K, IJzerman AP, Jacobson KA (2006) Structure–activity relationships of 1H-imidazo[4,5-c]quinolin-4-amine derivatives new as allosteric enhancers of the A3 adenosine receptor. J Med Chem 49:3354–3361

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Nikodijevic O, Shi D, Gallo-Rodriguez C, Olah ME, Stiles GL, Daly JW (1993) A role for central A3-adenosine receptors: mediation of behavioral depressant effects. FEBS Lett 336:57–60

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Siddiqi SM, Olah ME, Ji XD, Melman N, Bellamkonda K, Meshulmam Y, Stiles GL, Kim HO (1995) Structure–activity relationships of 9-alkyladenine and ribose modified adenosine derivatives at rat A3 adenosine receptors. J Med Chem 38:1720–1735

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Park KS, Jiang J-L, Kim YC, Olah ME, Stiles GL, Ji X-D (1997) Pharmacological characterization of novel A3 adenosine receptor-selective antagonists. Neuropharmacology 36:1157–1165

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Ji X-d, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG (2000) Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem 43:2196–2203

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Gao ZG, Chen A, Barak D, Kim SA, Lee K, Link A, Van Rompaey P, Van Calenbergh S, Liang BT (2001) Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A3 receptor with selectively enhanced affinity for amine-modified nucleosides. J Med Chem 44:4125–4136

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Ohno M, Duong HT, Kim SK, Tchilibon S, Cesnek M, Holy A, Gao ZG (2005) A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists. Chem Biol 12:237–247

    Article  CAS  PubMed  Google Scholar 

  • Jeong LS, Lee HW, Jacobson KA, Kim HO, Shin DH, Lee JA, Gao ZG, Lu C, Duong HT, Gunaga P, Lee SK, Jin DZ, Chun MW, Moon HR (2006a) Structure–activity relationships of 2-chloro-N 6-substituted-4′-thioadenosine-5′-uronamides as highly potent and selective agonists at the human A3 adenosine receptor. J Med Chem 49:273–281

    Article  CAS  PubMed  Google Scholar 

  • Jeong LS, Lee HW, Kim HO, Jung JY, Gao ZG, Duong HT, Rao S, Jacobson KA, Shin DH, Lee JA, Gunaga P, Lee SK, Jin DZ, Chun MW (2006b) Design, synthesis, and biological activity of N 6-substituted-4′-thioadenosines at the human A3 adenosine receptor. Bioorg Med Chem 14:4718–4730

    Article  CAS  PubMed  Google Scholar 

  • Jeong LS, Choe SA, Gunaga P, Kim HO, Lee HW, Lee SK, Tosh DK, Patel A, Palaniappan KK, Gao ZG, Jacobson KA, Moon HR (2007) Discovery of a new nucleoside template for human A3 adenosine receptor ligands: D-4′-thioadenosine derivatives without 4′-hydroxymethyl group as highly potent and selective antagonists. J Med Chem 50:3159–3162

    Article  CAS  PubMed  Google Scholar 

  • Jeong LS, Lee HW, Kim HO, Tosh D, Pal S, Choi WJ, Gao ZG, Patel AR, Williams W, Jacobson KA, Kim HD (2008) Structure–activity relationships of 2-chloro-N 6-substituted-4′-thioadenosine-5′-N, N-dialkyluronamides as human A3 adenosine receptor antagonists. Bioorg Med Chem 18:1612–1616

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Jung K-Y, Kim S-K, Gao Z-G, Gross AS, Melman N, Jacobson KA, Kim YC (2004) Structure–activity relationships of thiazole and thiadiazole derivatives as potent and selective human adenosine A3 receptor antagonists. Bioorg Med Chem 12:613–623

    Article  CAS  PubMed  Google Scholar 

  • Kim HO, Ji X-D, Siddiqi SM, Olah ME, Stiles GL, Jacobson KA (1994a) 2-Substitution of N 6-benzyladenosine-5′-uronamides enhances selectivity for A3-adenosine receptors. J Med Chem 37:3614–3621

    Article  CAS  PubMed  Google Scholar 

  • Kim HO, Ji X-D, Melman N, Olah ME, Stiles GL, Jacobson KA (1994b) Selective ligands for rat A3-adenosine receptors: structure–activity relationships of 1,3-dialkylxanthine-7-riboside derivatives. J Med Chem 37:4020–4030

    Article  CAS  PubMed  Google Scholar 

  • Kim YC, Ji X-D, Jacobson KA (1996) Derivatives of the triazoloquinazoline adenosine antagonist (CGS15943) are selective for the human A3 receptor subtype. J Med Chem 39:4142–4148

    Article  CAS  PubMed  Google Scholar 

  • Kim SK, Gao Z-G, Van Rompaey P, Gross AS, Chen A, Van Calenbergh S, Jacobson KA (2003) Modeling the adenosine receptors: comparison of binding domains of A2A agonist and antagonist J Med Chem 46:4847–4859

    Google Scholar 

  • Kim SK, Gao ZG, Jeong LS, Jacobson KA (2006) Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor. J Mol Graph Model 25:562–577

    Article  CAS  PubMed  Google Scholar 

  • Lee K, Ravi RG, Ji X-D, Marquez VE, Jacobson KA (2001) Ring-constrained (N)methanocarba-nucleosides as adenosine receptor agonists: independent 5′-uronamide and 2′-deoxy modifications. Bioorg Med Chem Lett 11:1333–1337

    Article  CAS  PubMed  Google Scholar 

  • Lenzi O, Colotta V, Catarzi D, Varano F, Filacchioni G, Martini C, Trincavelli L, Ciampi O, Varani K, Marighetti F, Morizzo E, Moro S (2006) 4-Amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as new potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand–receptor modeling studies. J Med Chem 49:3916–3925

    Article  CAS  PubMed  Google Scholar 

  • Li AH, Moro S, Melman N, Ji XD, Jacobson KA (1998) Structure–activity relationships and molecular modeling of 3,5-diacyl-2,4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists. J Med Chem 41:3186–3201

    Article  CAS  PubMed  Google Scholar 

  • Lopes LV, Rebola N, Pinheiro PC, Richardson PJ, Oliveira CR, Cunha RA (2003) Adenosine A3 receptors are located in neurons of the rat hippocampus. Neuroreport 14:1645–1648

    Article  CAS  PubMed  Google Scholar 

  • Maconi A, Pastorin G, Da Ros T, Spalluto G, Gao ZG, Jacobson KA, Baraldi PG, Cacciari B, Varani K, Moro S, Borea PA (2002) Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A3 adenosine receptor antagonist. J Med Chem 45:3579–82

    Article  CAS  PubMed  Google Scholar 

  • Marquez VE, Siddiqui MA, Ezzitouni A, Russ P, Wang J, Wagner RW, Matteucci MD (1996) Nucleosides with a twist. Can fixed forms of sugar ring pucker influence biological activity in nucleosides and oligonucleotides. J Med Chem 39:3739–3747

    CAS  Google Scholar 

  • Matot I, Weininger CF, Zeira E Galun E, Joshi BV, Jacobson KA (2006) A3 Adenosine receptors and mitogen activated protein kinases in lung injury following in-vivo reperfusion. Crit Care 10:R65, doi:10.1186/cc4893

    Google Scholar 

  • Melman, A, Gao, ZG, Kumar, D, Wan, TC, Gizewski, E, Auchampach, JA, Jacobson, KA (2008a) Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists. Bioorg Med Chem Lett 18:2813–2819

    Article  CAS  PubMed  Google Scholar 

  • Melman A, Wang B, Joshi BV, Gao ZG, de Castro S, Heller CL, Kim SK, Jeong LS, Jacobson KA (2008b) Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system. Bioorg Med Chem 16:8546–8556

    Article  CAS  PubMed  Google Scholar 

  • Meyerhof W, Müller-Brechlin R, Richter D (1991) Molecular cloning of a novel putative G-protein coupled receptor expressed during rat spermiogenesis. FEBS Lett 284:155–160

    Article  CAS  PubMed  Google Scholar 

  • Moro S, Braiuca P, Deflorian F, Ferrari C, Pastorin G, Cacciari B, Baraldi PG, Varani K, Borea PA, Spalluto G (2005) Combined target-based and ligand-based drug design approach as a tool to define a novel 3D-pharmacophore model of human A3 adenosine receptor antagonists: pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as a key study. J Med Chem 48:152–162

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Müller CE, Thorand M, Qurishi R, Diekmann M, Jacobson KA, Padgett WL, Daly JW (2002a) Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A2A- and A3-adenosine receptor antagonists. J Med Chem 45:3440–3450

    Article  PubMed  CAS  Google Scholar 

  • Müller CE, Diekmann M, Thorand M, Ozola V (2002b) [3H]8-Ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]-purin-5-one ([3H]PSB-11), a novel high affinity antagonist radioligand for human A3 adenosine receptors. Bioorg Med Chem Lett 12:501–503

    Article  PubMed  Google Scholar 

  • Müller CE (2003) Medicinal chemistry of adenosine A3 receptor ligands. Curr Top Med Chem 3:445–462

    Article  PubMed  Google Scholar 

  • Novellino E, Barbara Cosimelli, Marina Ehlardo, Giovanni Greco, Manuela Iadanza, Antonio Lavecchia, Rimoli MG, Sala A, Da Settimo A, Primofiore G, Da Settimo F, Taliani S, La Motta C, Klotz KN, Tuscano D, Trincavelli ML, Martini C (2005) 2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists at human A1 and A3 adenosine receptors designed by 3D database searching. J Med Chem 48:8253–8260

    Article  CAS  PubMed  Google Scholar 

  • Ohana G, Bar-Yehuda S, Barer F, Fishman P (2001) Differential effect of adenosine on tumor and normal cell growth: focus on the A3 adenosine receptor. J Cell Physiol 186:19–23

    Article  CAS  PubMed  Google Scholar 

  • Ohno M, Gao ZG, Van Rompaey P, Tchilibon S, Kim SK, Harris BA, Blaustein J, Gross AS, Duong HT, Van Calenbergh S, Jacobson KA (2004) Modulation of adenosine receptor affinity and intrinsic efficacy in nucleosides substituted at the 2-position. Bioorg Med Chem 12: 2995–3007

    Article  CAS  PubMed  Google Scholar 

  • Okamura K, Kurogi Y, Nishikawa H, Hashimoto K, Fujiwara H, Nagao Y (2002) 1,2,4-triazolo[5,1-i]purine derivatives as highly potent and selective human adenosine A3 receptor ligands. J Med Chem 45:3703–3708

    Article  CAS  PubMed  Google Scholar 

  • Okamura T, Kurogi Y, Hashimoto K, Nagao Y (2004a) Facile synthesis of fused 1,2,4-triazolo[1,5-c]-pyrimidine derivatives as human adenosine A3 receptor ligands. Bioorg Med Chem Lett 14:2443–2446

    Article  CAS  PubMed  Google Scholar 

  • Okamura T, Kurogi Y, Hashimoto K, Sato S, Nishikawa H, Kiryu K, Nagao Y (2004b) Structure-activity relationships of adenosine A3 receptor ligands: new potential therapy for the treatment of glaucoma. Bioorg Med Chem Lett 14:3775–3779

    Article  CAS  PubMed  Google Scholar 

  • Ozola V, Thorand M, Diekmann M, Qurishi R, Schumacher B, Jacobson KA, Müller CE (2003) 2-Phenylimidazo[2,1-i]purin-5-ones: structure–activity relationships and characterization of potent and selective inverse agonists at human A3 adenosine receptors. Bioorg Med Chem 11:347–356

    Article  CAS  PubMed  Google Scholar 

  • Pastorin G, Da Ros T, Bolcato C, Montopoli C, Moro S, Cacciari B, Baraldi PG, Varani K, Borea PA, Spalluto G (2006) Synthesis and biological studies of a new series of 5 heteroarylcarbamoylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as human A3 adenosine receptor antagonists. Influence of the heteroaryl substituent on binding affinity and molecular modeling investigations. J Med Chem 49:1720–1729

    CAS  Google Scholar 

  • Perreira M, Jiang J, Klutz AM, Gao ZG, Shainberg A, Lu C, Thomas CJ, Jacobson KA (2005) Reversine and its 2-substituted adenine derivatives as potent and selective A3 adenosine receptor antagonists. J Med Chem 48:4910–4918

    Article  CAS  PubMed  Google Scholar 

  • Press NJ, Keller TH, Tranter P, Beer D, Jones K, Faessler A, Heng R, Lewis C, Howe T, Gedeck P, Mazzoni L, Fozard JR (2004) New highly potent and selective adenosine A3 receptor antagonists. Curr Top Med Chem 4:863–870

    Article  CAS  PubMed  Google Scholar 

  • Priego EM, von Frijtag Drabbe Kuenzel J, IJzerman AP, Camarasa MJ, Pérez-Pérez MJ (2002) Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A3 adenosine receptor antagonists. J Med Chem 45:3337–3344

    Article  CAS  PubMed  Google Scholar 

  • Pugliese AM, Coppi E, Volpini R, Cristalli G, Corradetti R, Jeong LS, Jacobson KA, Pedata F (2007) Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen-glucose deprivation episodes of different duration. Biochem Pharmacol 74:768–779

    Article  CAS  PubMed  Google Scholar 

  • Saki M, Tsumuki H, Nonaka H, Shimada J, Ichimura M (2002) KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride), a new potent and selective adenosine A3 receptor antagonist. Eur J Pharmacol 444:133–144

    Article  CAS  PubMed  Google Scholar 

  • Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson, RG (1993) Molecular cloning and characterization of the human A3 adenosine receptor. Proc Natl Acad Sci 90:10365–10369

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA (2002) Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem 277:40989–40996

    Article  CAS  PubMed  Google Scholar 

  • Shneyvais V, Mamedova L, Zinman T, Jacobson KA, Shainberg A (2001) Activation of A3 adenosine receptor protects against doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol 33:1249–1261

    Article  CAS  Google Scholar 

  • Siddiqi SM, Jacobson KA, Esker JL, Olah ME, Ji XD, Melman N, Tiwari KN, Secrist JA III, Schneller SW, Cristalli G, Stiles GL, Johnson Cr, IJzerman AP (1995) Search for new purine- and ribose-modified adenosine analogues as selective agonists and antagonists at adenosine receptors. J Med Chem 38:1174–1188

    Article  CAS  PubMed  Google Scholar 

  • Strickler J, Jacobson KA, Liang BT (1996) Direct preconditioning of cultured chick ventricular myocytes: novel functions of cardiac adenosine A2A and A3 receptors. J Clin Invest 98: 1773–1779

    Article  CAS  PubMed  Google Scholar 

  • Tafi A, Bernardini C, Botta M, Corelli F, Andreini M, Martinelli A, Ortore G, Baraldi PG, Fruttarolo F, Borea PA, Tuccinardi T (2006) Pharmacophore based receptor modeling: the case of adenosine A3 receptor antagonists. An approach to the optimization of protein models. J Med Chem 49:4085–4097

    CAS  Google Scholar 

  • Tchilibon S, Kim SK, Gao ZG, Harris BA, Blaustein J, Gross AS, Melman N, Jacobson KA (2004) Exploring distal regions of the A3 adenosine receptor binding site: sterically-constrained N 6-(2-phenylethyl)adenosine derivatives as potent ligands. Bioorg Med Chem 12: 2021–2034

    Article  CAS  PubMed  Google Scholar 

  • Tchilibon S, Joshi BV, Kim SK, Duong HT, Gao ZG, Jacobson KA (2005) (N)-Methanocarba 2,N 6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists. J Med Chem 48:1745–1758

    Article  CAS  PubMed  Google Scholar 

  • Tracey WR, Magee WP, Oleynek JJ, Hill RJ, Smith AH, Flynn DM, Knight DR (2003) Novel N 6-substituted adenosine 5′-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury. Am J Physiol Heart Circ Physiol 285: H2780–H2787

    CAS  PubMed  Google Scholar 

  • van Galen PJM, van Bergen AH, Gallo-Rodriguez C, Melman N, Olah ME, IJzerman AP, Stiles GL, Jacobson KA (1994) A binding site model and structure–activity relationships for the rat A3 adenosine receptor. Mol Pharmacol 45:1101–1111

    PubMed  Google Scholar 

  • van Muijlwijk-Koezen JE, Timmerman H, Link R, von der Goot H, Menge WMPB, von Frijtag von Drabbe Künzel JK, de Groote M, IJzerman AP (2000) Isoquinoline and quinazoline urea analogues as antagonists for the human adenosine A3 receptor. J Med Chem 43:2227–2238

    Google Scholar 

  • van Muijlwijk-Koezen JE, Timmerman H, Vollinga RC, von Drabbe Künzel JF, de Groote M, Visser S, IJzerman AP (2001) Thiazole and thiazole analogues as novel class of adenosine receptor antagonists. J Med Chem 44:749–762

    Article  PubMed  CAS  Google Scholar 

  • Van Rompaey P, Jacobson KA, Gross AS, Gao ZG, Van Calenbergh S (2005) Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety. Bioorg Med Chem 13:973–983

    Article  PubMed  CAS  Google Scholar 

  • van Tilburg EW, von Frijtag Drabbe Kunzel J, de Groote M, IJzerman AP (2002) 2, 5′-Disubstituted adenosine derivatives: evaluation of selectivity and efficacy for the adenosine A1, A2A, and A3 receptor. J Med Chem 45:420–429

    Article  PubMed  CAS  Google Scholar 

  • Varani K, Merighi S, Gessi S, Klotz KN, Leung E, Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Borea PA (2000) [3H]MRE 3008F20: a novel antagonist radioligand for the pharmacological and biochemical characterization of human A3 adenosine receptors. Mol Pharmacol 57: 968–975

    CAS  PubMed  Google Scholar 

  • Volpini R, Costanzi S, Lambertucci C, Taffi S, Vittori S, Klotz KN, Cristalli G (2002) N 6-Alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A3 receptor and a starting point for searching A2B ligands. J Med Chem 45:3271–3279

    Article  CAS  PubMed  Google Scholar 

  • Volpini R, Dal Ben D, Lambertucci C, Taffi S, Vittori S, Klotz KN, Cristalli GJ (2007) N 6-Methoxy-2-alkynyladenosine derivatives as highly potent and selective ligands at the human A3 adenosine receptor. J Med Chem 50:1222–1230

    Article  CAS  PubMed  Google Scholar 

  • Yaar R, Lamperti ED, Toselli PA, Ravid K (2002) Activity of the A3 adenosine receptor gene promoter in transgenic mice: characterization of previously unidentified sites of expression. FEBS Lett 532:267–272

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Avila MY, Peterson-Yantorno K, Coca-Prados M, Stone RA, Jacobson KA, Civan MM (2005) The cross-species A3 adenosine-receptor antagonist MRS1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure. Curr Eye Res 30: 747–754

    Article  CAS  PubMed  Google Scholar 

  • Zhou QY, Li C, Olah ME, Johnson RA, Stiles GL, Civelli O (1992) Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc Natl Acad Sci USA 89:7432–7436

    Article  CAS  PubMed  Google Scholar 

  • Zhu R, Frazier CR, Linden J, Macdonald TL (2006) N 6-Ethyl-2-alkynyl NECAs, selective human A3 adenosine receptor agonists. Bioorg Med Chem Lett 16:2416–2418

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Author information

Authors and Affiliations

  1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD, 20892-0810, USA

    Kenneth A. Jacobson

  2. Bldg. 8A, Rm. B1A-23, NIH, NIDDK, LBC, Bethesda, MD, 20892-0810, USA

    Athena M. Klutz, Dilip K. Tosh & Andrei A. Ivanov

  3. Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100, Ferrara, Italy

    Delia Preti & Pier Giovanni Baraldi

Authors
  1. Kenneth A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Athena M. Klutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dilip K. Tosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrei A. Ivanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Delia Preti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pier Giovanni Baraldi
    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. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Jacobson, K.A., Klutz, A.M., Tosh, D.K., Ivanov, A.A., Preti, D., Baraldi, P.G. (2009). Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_5

Download citation

Publish with us

Policies and ethics

Search

Navigation