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Adenosine Receptors in Health and Disease pp 1–24Cite as

Introduction to Adenosine Receptors as Therapeutic Targets

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

Abstract

Adenosine acts as a cytoprotective modulator in response to stress to an organ or tissue. Although short-lived in the circulation, it can activate four subtypes of G protein-coupled adenosine receptors (ARs): A1, A2A, A2B, and A3. The alkylxanthines caffeine and theophylline are the prototypical antagonists of ARs, and their stimulant actions occur primarily through this mechanism. For each of the four AR subtypes, selective agonists and antagonists have been introduced and used to develop new therapeutic drug concepts. ARs are notable among the GPCR family in the number and variety of agonist therapeutic candidates that have been proposed. The selective and potent synthetic AR agonists, which are typically much longer lasting in the body than adenosine, have potential therapeutic applications based on their anti-inflammatory (A2A and A3), cardioprotective (preconditioning by A1 and A3 and postconditioning by A2B), cerebroprotective (A1 and A3), and antinociceptive (A1) properties. Potent and selective AR antagonists display therapeutic potential as kidney protective (A1), antifibrotic (A2A), neuroprotective (A2A), and antiglaucoma (A3) agents. AR agonists for cardiac imaging and positron-emitting AR antagonists are in development for diagnostic applications. Allosteric modulators of A1 and A3 ARs have been described. In addition to the use of selective agonists/antagonists as pharmacological tools, mouse strains in which an AR has been genetically deleted have aided in developing novel drug concepts based on the modulation of ARs.

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Abbreviations

ADHF:

Acute decompensated heart failure

ADP:

Adenosine diphosphate

AMP:

Adenosine 5′-monophosphate

AMP579:

[1S-[1α, 2β, 3β, 4α(S*)]]-4-[7-[[1-[(3-Chlorothien-2-yl)methyl] propyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]-N-ethyl 2,3-dihydroxycyclopentanecarboxamide

AR:

Adenosine receptor

ATP:

Adenosine triphosphate

BAY 60–6583:

2-[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl] pyridin-2-ylsulfanyl]acetamide

BAY 68–4986:

6-Amino-2-(2-(4-chlorophenyl)thiazol-4-ylthio)-4-(4- (2-hydroxyethoxy)phenyl)-5-isocyanonicotinonitrile

BG9719:

1,3-Dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine

BG9928:

3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid

BIIB014:

3-(4-Amino-3-methylbenzyl)-7-(2-furyl)-3H- [1,2,3]triazolo [4,5-d ]pyrimidine-5-amine (V2006)

CD39:

Apyrase

CD73:

Ecto-5′-nucleotidase

CF101:

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

CF102:

2-Chloro-N 6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (Cl-IB-MECA)

CP-608,039:

(2S, 3S, 4R, 5R)-3-Amino-5-{6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl-l- 4-hydroxytetrahydrofuran-2-carboxylic acid methylamide

CP-532,903:

(2S, 3S, 4R, 5R)-3-Amino-5-{6-[2,5-dichlorobenzylamino]purin-9-yl-l-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide

CPFPX:

8-Cyclopentyl-1-propyl-3-(3-fluoropropyl)-xanthine

CVT-3146:

1-[6-Amino-9-[(2R, 3R, 4S, 5R)-3,4-dihydroxy- 5-(hydroxymethyl)oxolan-2-yl]purin-2-yl]-N-methylpyrazole- 4-carboxamide

CVT-6883:

3-Ethyl-1-propyl-8-[1-(3-trifluoromethylbenzyl)-1H-pyrazol- 4-yl]-3,7-dihydropurine-2,6-dione

EL:

Extracellular loop

ENT:

Equilibrative nucleoside transporter

E-NTPDase:

Ectonucleoside triphosphate diphosphohydrolase

ERK:

Extracellular receptor signal-induced kinase

FK 453:

\((+)\mbox{ -}(R)\)-(1-(E)-3-(2-Phenylpyrazolo(1,5-a)pyridin-3-yl)acryl)-2-piperidine ethanol

FR194921:

2-(1-Methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin- 3-yl)-3(2H)-pyridazinone

GPCRs:

G protein-coupled receptors

GR79236:

N 6-[(1S, 2S)-2-Hydroxycyclopentyl]adenosine

GRKs:

G-protein-coupled receptor kinases

IL:

Intracellular loop

KW3902:

8-(Noradamantan-3-yl)-1,3-dipropylxanthine

KW6002:

8-[(E)-2-(3,4-Dimethoxyphenyl)vinyl]-1,3-diethyl- 7-methylpurine-2,6-dione

L-97-1:

3-[2-(4-Aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione

MAP:

Mitogen-activated protein

MAPK:

Mitogen-activated protein kinases

MRE0094:

2-[2-(4-Chlorophenyl)ethoxy]adenosine

MRE-0470:

2-[{Cyclohexylmethylene}hydrazino]adenosine (WRC-0470, binodenoson)

MRS5147:

\(({1}^{{\prime}}R,{2}^{{\prime}}R,{3}^{{\prime}}S,{4}^{{\prime}}R,{5}^{{\prime}}S)\mbox{ -}{4}^{{\prime}}\)-[2-Chloro-6-(3-bromobenzylamino)-purine]-2′, 3′-O-dihydroxybicyclo-[3.1.0]hexane

N-0861:

( ± )-N 6-Endonorbornan-2-yl-9-methyladenine

NNC-21-0136:

2-Chloro-N 6-[(R)-[(2-benzothiazolyl)thio]-2-propyl]-adenosine

OT-7999:

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

PET:

Positron emission tomography

PI3K:

Phosphoinositide-3 kinase

T-62:

(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)- (4-chlorophenyl)-methanone

SLV-320:

4-[(2-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-trans-cyclohexanol

SDZ WAG94:

N 6-Cyclohexyl-2′-O-methyl-adenosine

TM:

Transmembrane helix

VER6947:

2-Amino-N-benzyl-6-(furan-2-yl)-9H-purine-9-carboxamide

VER7835:

2-Amino-6-(furan-2-yl)-N-(thiophen-2-ylmethyl)-9H-purine- 9-carboxamide

V2006:

see BIIB014

WRC-0571:

8-(N-Methylisopropyl)amino-N 6-(5′-endohydroxy- endonorbornan-2-yl-9-methyladenine

ZM241385:

4-2-[7-Amino-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-yl-amino]ethylphenol

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Acknowledgements

Support from the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases is gratefully acknowledged. Dr. Andrei A. Ivanov, NIDDK, prepared the image shown in Fig. 2. Dr. Zhang-Guo Gao and Dr. Dale Kiesewetter are acknowledged for helpful discussions.

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

    Kenneth A. Jacobson

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Correspondence to Kenneth A. Jacobson .

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  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

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Jacobson, K.A. (2009). Introduction to Adenosine Receptors as Therapeutic Targets. 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_1

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