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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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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