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Adenosine Receptors

There are four known subtypes of adenosine receptors, referred to as A1, A2A, A2B and A3. All are members of the superfamily of G protein-coupled receptors and each bears the characteristic motif of seven transmembrane spanning domains. Modulation of adenosine receptors by selective agonists and antagonists has potential for the treatment of various cardiovascular, inflammatory and neurological diseases. For example, adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart by activating A1 and A3 receptors. A synthetic adenosine receptor agonist might therefore be beneficial to the survival of the ischemic heart. A3 receptor agonists are also a target for cancer therapy. A2A receptor agonists suppress excessive inflammation and reperfusion injury and may be useful also in physiologic stress testing. In the asthmatic lung, however, adenosine acts as an irritant and bronchoconstrictor, such that a synthetic adenosine receptor antagonist would be desirable.

Selectivity for A1 receptors is typically accomplished through modification of the N6-position that gave rise to compounds such as CPA, CHA, and R-PIA, although substantial A3 receptor affinity was later detected for these agonists. The 2-chloro analog CCPA displays slightly greater A1 receptor affinity than the parent CPA. S(-)-ENBA is a highly potent and selective A1 receptor agonist. The affinities of these N6-substituted derivatives at A3 receptors are often intermediate between their respective A1 and A2A affinities. Although most N6-substituted adenosine agonists are A1-selective, the agonist DPMA is 30-fold selective for the rat A2A receptor.

Small alkyl amide substitution at the 5'-position, as in NECA, provides increased potency at all of the adenosine receptors. NECA is also among the most potent agonists at all four subtypes of adenosine receptors and is therefore non-selective. CGS21680 is a moderately A2A-selective adenosine agonist in rat but not human, possessing a 140-fold selectivity for A2A versus A1 receptors in rat. Aryl amines related to the agonist CGS21680 (e.g. PAPA-APEC) or the antagonist ZM241,385 can be radioiodinated to provide A2A receptor-selective radioligands.

The most recently discovered member of the adenosine receptor family, the A3 receptor, has a unique pharmacological profile, tissue distribution and effector coupling. In recent years, selective A3 adenosine receptor agonists and antagonists have been described. Previously, APNEA had been used as an agent to activate A3 receptors in the presence of non-A3 antagonists, although APNEA is actually 8-fold selective for A1 receptors. IB-MECA is 50-fold selective for A3 versus either A1 or A2A receptors in vitro and appears to be highly A3 selective in vivo. The related 4-amino derivative may be radioiodinated giving rise to [125I]-I-AB-MECA which is widely used as a high affinity radioligand for A3 receptors. 2-Chloro substitution, in combination with modifications at N6 and 5'-positions, e.g. in Cl-IB-MECA (selective for rat A3 vs A1 and A2A receptors by 2500- and 1400-fold, respectively), further enhances A3 selectivity.

Adenosine receptor antagonists, of which xanthines and numerous classes of fused heterocyclic compounds are representative, have been under development as anti-asthmatic, anti-arrhythmic, renal-protective, anti-Parkinson’s and cognition enhancing drugs. A3 receptor antagonists have potential in treating glaucoma or inflammatory disorders.

The classical xanthines, theophylline (1,3-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine) are non-selective adenosine receptor antagonists possessing low micromolar affinity. Selective antagonists for A1 receptors include many 8-aryl and 8-cycloalkyl xanthine derivatives, such as CPX which is ~500-fold selective for A1 versus A2A receptors. Certain non-xanthine antagonists, such as N-0841, are A1 selective, whereas SCH-58261 is a highly potent and selective A2A receptor antagonist. CSC and other 8-styrylxanthines, such as KW 6002, are selective for A2A receptors versus both A1 and A2B receptors. However, in dilute solution, these compounds suffer from sensitivity to photoisomerization.

At A3 receptors, the dihydropyridine derivative MRS 1191 (not active at L-type calcium channels) and the triazoloquinazoline MRS 1220 (not selective in rat) are both relatively potent A3 receptor antagonists, possessing Ki values of 31 and 0.65 nM, respectively, at the human subtype. The nucleoside MRS 1292 and the pyridine derivative MRS 1523 are selective A3 adenosine receptor antagonists in the rat and human.


The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Currently Accepted Name A1 A2A A2B A3
Alternate Names Ri A2a, Ra A2b  
Structural Information 326 aa (human) 412 aa (human) 332 aa (human) 318 aa (human)
Receptor Selective Agonists Adenosine amine congener (A111)
CPA (C8031)
CHA (C9901)
CCPA (C7938)
R-PIA (P4532)
S(-)-ENBA (E111)
CGS21680 (C141)
NECAb (E2387)
IB-MECA (I146)
Cl-IB-MECA (C277)
Receptor Selective Antagonists CPX (C101)
CPT (C102)
KW 6002
8-(3-Chlorostyryl)caffeine (C197)
SCH-58261 (S4568)
XACb (X103)
Alloxazine (A28651)
MRS 1754 (M6316)
MRE 2029-F20
MRS 1191 (M227)
MRS 1220 (M228)
MRS 1523 (M1809)
VUF 5574 (V5888)
MRS 1292
MRE 3008F20
Signal Transduction Mechanisms Gi (cAMP modulation)
increased K+, decreased Ca2+
Gs (increase cAMP) Gs (increase cAMP)
increased Ca2+
Gi (cAMP modulation)
increased Ca2+
Radioligands of Choice [3H]-CHA
[3H]-MRS 1754
[3H]-MRE 2029-F20
Tissue Expression Cerebral cortex, hippocampus, atria, kidneys, testes, adipocytes Platelets, endothelial cells, striatum, neutrophils Fibroblasts, colon, aorta, mast cells Eosinophils, heart, lung, pineal
Physiological Function Inhibition of neurotransmitter release, bradycardia, ischemic preconditioning Vasodilatation, inhibition of platelet aggregation, sensorimotor integration Smooth muscle relaxation, release from mast cells Ischemic preconditioning
Disease Relevance Cardiac arrhythmia, diabetes, stroke Parkinson’s disease, inflammation, arthritis, neurodegeneration Asthma, diabetes Cardiac ischemia, cancer, arthritis, glaucoma



a) HE-NECA is also a potent agonist at A3 receptors.

b) NECA and XAC are among the most potent agents at this adenosine receptor subtype. However, these compounds are not subtype selective.

c) Rat A3 receptor is relatively insensitive to xanthine blockade.



AB-MECA: N6-(4-Aminobenzyl)-9-[5-(methylcarbamoyl)-β-D-ribofuranosyl]adenine
ATL-146e: 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester
CCPA: 2-Chloro CPA
CGS21680: 2-p-(2-Carboxyethyl)phenethylamino-5’-N-ethylcarboxamidoadenosine
CHA: N6-Cyclohexyladenosine
Cl-IB-MECA: 2-Chloro-N6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-β-D-ribofuranosyl]adenine
CPA: N6-Cyclopentyladenosine
CPT: 8-Cyclopentyl-1,3-dimethylxanthine
CPX: 8-Cyclopentyl-1,3-dipropylxanthine
CVT-510: N-(3(R)-Tetrahydrofuranyl)-6-aminopurine riboside
CVT-3146: 1-(6-Amino-9-β-D-ribofuranosyl-9H-purin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide (regadenosine)
DBXRM: 1,3-Dibutylxanthine 7-riboside 5'-N-methylcarboxamide
DPMA: N6-[2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine
S(-)-ENBA: (2S)-N6-[2-endo-Norbornyl]adenosine
HE-NECA: 2-Hexynyl-adenosine-5’-N-ethyluronamide
I-ABOPX: 3-(3-Iodo-4-aminobenzyl)-8-(4-oxyacetate)-phenyl-1-propyl xanthine
IB-MECA: N6-(3-Iodobenzyl)-9-[5-(methylcarbamoyl)-β-D-ribofuranosyl]adenine
KW 6002: (E)-1,3-Diethyl-8-(3,4-dimethoxyphenylethyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione
MRE 2029-F20: N-Benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide
MRE 3008F20: 5N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
MRS 1191: 3-Ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate
MRS 1220: 9-Chloro-2-(2-furyl)-5-phenylacetylamino[1,2,4]-triazolo[1,5-c]quinazoline
MRS 1292: (2R,3R,4S,5S)-2-[N6-3-Iodobenzyl)adenos-9'-yl]-7-aza-1-oxa-6-oxospiro[4.4]-nonan-4,5-diol
MRS 1523: 2,3-Diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate
MRS 1754: 8-[4-[[(4-Cyano)phenylcarbamoylmethyl]oxy]phenyl]-1,3-di-(n-propyl)xanthine
N-0840: N6-Cyclopentyl-9-methyladenine
NECA: N-Ethylcarboxamidoadenosine
PAPA-APEC: 1-[6-Amino-2-[[2-[4-[3-[[2-[[(4-aminophenyl)acetyl]amino]ethyl]amino]-3-oxopropyl]phenyl]ethyl]amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide
PIA: R(–)-N6-(2-Phenylisopropyl)adenosine
SCH-58261: 5-Amino-7-(β-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
VUF 5574: N-(2-Methoxyphenyl)-N'-(2-(3-pyridyl)quinazolin-4-yl)urea
WRC-0571: 8-(N-Methylisopropyl)amino-N-(5’-endohydroxy-endonorbornyl)-9-methyladenine
XAC: 8-[4-[[[[(2-Aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine; Xanthine amine congener
ZM241,385: 4-[2-(7-Amino-2-(2-furyl)[1,2,4-triazolo[2,3-a] [1,3,5]triazin-5-yl-amino]ethyl phenol


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