Adenosine

Overview: Adenosine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adenosine Receptors; Fredholm et al., 2001) are activated by the endogenous ligand adenosine (potentially inosine also at A₃ receptors). NECA is a non-selective agonist, while XAC and CGS15943 display submicromolar affinity at all four adenosine receptors (Klotz et al., 1998; Ongini et al., 1999). A crystal structure for the A_2A receptor has recently been described (Jaakola et al., 2008).

Nomenclature	A1	A2A	A2B	A3
Ensembl ID	ENSG00000163485	ENSG00000128271	ENSG00000170425	ENSG00000121933
Principal transduction	Gi/o	Gs	Gs	Gi/o
Selective agonists	CPA, CCPA, S-ENBA, GR79236	CGS21680, HENECA, ATL-146e (Peirce et al., 2001)	Bay60-6583 (Eckle et al., 2007)	2-Cl-IB-MECA, IB-MECA
Selective antagonists	PSB36 (9.8, Abo-Salem et al., 2004), DPCPX (8.5), SLV320 (9.0, Kalk et al., 2007)	SCH442416 (10.3, Todde et al., 2000), ZM241385 (9.0), SCH58261 (7.9–9.5)	PSB603 (9.3, Borrmann et al., 2009), MRS1754 (8.7), MRS1706 (8.4), PSB1115 (7.7)	MRS1220 (8.8), VUF5574 (8.4, van Muijlwijk-Koezen et al., 2000), MRS1523 (7.7), MRS1191 (7.0)
Probes	[3H]-CCPA, [3H]-DPCPX (0.6–1.2 nM)	[3H]-CGS21680, [3H]-ZM241385 (0.8 nM)	[3H]-MRS1754 (1.1 nM)	[125I]-AB-MECA (0.6 nM)

Adenosine inhibits many intracellular ATP-utilizing enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A_2B adenosine receptor (ENSG00000182537) with 79% identity to the A_2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor (Jacobson et al., 1995). DPCPX also exhibits antagonism at A_2B receptors (pK_ica 7, Alexander et al., 1996; Klotz et al., 1998). HENECA also shows activity at A₃ receptors (Varani et al., 1998). Antagonists at A₃ receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A₃ receptor. In the absence of other adenosine receptors, [³H]-DPCPX and [³H]-ZM241385 can also be used to label A_2B receptors (K_Dca 30 and 60 nM respectively). [¹²⁵I]-AB-MECA also binds to A₁ receptors (Klotz et al., 1998). [³H]-CGS21680 is relatively selective for A_2A receptors, but may also bind to other sites in cerebral cortex (Johansson and Fredholm, 1995; Cunha et al., 1996). [³H]-NECA binds to other non-receptor elements, which also recognize adenosine (e.g. Lorenzen et al., 1996). XAC-BY630 has been described as a fluorescent antagonist for labelling A₁ adenosine receptors in living cells, although activity at other adenosine receptors was not examined (Briddon et al., 2004).

Adenosine has also been reported to act as a partial agonist at the ghrelin receptor (Smith et al., 2000), but this has been questioned (Johansson et al., 2005).

Glossary

Abbreviations:

2Cl-IB-MECA

2-chloro-N⁶-(3-iodobenzyl)adenosine-5′-N-methyluronamide

AB-MECA

N⁶-(4-aminobenzyl)-adenosine-5′-N-methyluronamide

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

Bay60-6583

2-(6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl) pyridin-2-ylthio)acetamide

CCPA

2-chloro-N⁶-cyclopentyladenosine

CGS15943

5-amino-9-chloro-2-(2-furyl)1,2,4-triazolo[1,5-c]quinazoline

CGS21680

2-(4-[2-carboxyethyl]-phenethylamino)adenosine-5′-N-ethyluronamide

CPA

N⁶-cyclopentyladenosine

DPCPX

8-cyclopentyl-1,3-dipropylxanthine

GR79236

N-[(1s,2s)-2-hydroxycyclopentyl adenosine

HENECA

2-(1-(E)-hexenyl)adenosine-5′-N-ethyluronamide

MRS1191

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

MRS1220

9-chloro-2-(2-furyl)5-phenylacetylamino[1,2,4]triazolo[1,5c]quinazoline

MRS1523

2,3-ethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate

MRS1706

N-(4-acetylphenyl)-2-(4-[2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl]phenoxy)acetamide

MRS1754

8-(4-[{(4-cyanophenyl)carbamoylmethyl}oxy]phenyl)-1,3-di(n-propyl)xanthine

NECA

adenosine-5′-N-ethyluronamide

PSB1115

4-[2,3,6,7-tetrahydro-2,6-dioxo-1-propyl-1H-purin-8-yl)benzenesulphonic acid

PSB36

1-butyl-8-(3-noradamantanyl)-3-(3-hydroxypropyl)xanthine

PSB603

8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine

S-ENBA

(2S)-N⁶-(2-endonorbanyl)adenosine

SCH4421416

2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine

SCH58261

5-amino-2-(2-furyl)-7-phenylethyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,5c]pyrimidine

SLV320

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

VUF5574

N-(2-methoxyphenyl)-N-(2-[3-pyridyl]quinazolin-4-yl)urea

XAC

8-(4-[{([{2-aminoethyl}amino]carbonyl)methyl}oxy]phenyl)-1,3-dipropylxanthine; also known as xanthine amine congener

XAC-BY630

N-(2-aminoethyl)-2-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)phenoxy]acetamide

ZM241385

4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl amino]ethyl)phenol

Further Reading

Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001). International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev53: 527–552.

Fredholm BB, Chen JF, Masino SA, Vaugeois JM (2005). Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu Rev Pharmacol Toxicol45: 385–412.

Jacobson KA, Gao ZG (2006). Adenosine receptors as therapeutic targets. Nat Rev Drug Discovery5: 247–264.

Klinger M, Freissmuth M, Nanoff C (2002). Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. Cell Signal14: 99–108.

Latini S, Pedata F (2001). Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem79: 463–484.

Yaar R, Jones MR, Chen JF, Ravid K (2005). Animal models for the study of adenosine receptor function. J Cell Physiol202: 9–20.