International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Bertil B. Fredholm; Adriaan P. IJzerman; Kenneth A. Jacobson; Karl-Norbert Klotz; Joel Linden

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Figure 1
Dendrogram showing sequence similarity between cloned adenosine receptors. The figure is slightly redrawn from that available athttp://www.gpcr.org/7tm/seq/007_001/001_007_001.TREE.html. This phylogenetic tree was automatically calculated by WHAT IF based on a neighbor-joining algorithm.
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Figure 2
Protein backbone representations of the structures of bacteriorhodopsin (A) and rhodopsin (B) as retrieved from the Brookhaven Protein Data Bank (1C3W and 1F88, respectively).
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Figure 3
Computer modeling of CPA (yellow), human A₁ adenosine receptor interactions. Only helices III (left) and VII (right) are shown (both in green) with relevant residues (half-bond colors).
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Figure 4
Structures of reference compounds used to classify adenosine receptors. Panel A, structure of some non-selective and A₁ receptor-selective adenosine analogs; panel B, structure of adenosine analogs used to classify A_2A and A₃ receptors; panel C, structure of selected adenosine receptor antagonists.

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Table 1

Current adenosine receptor nomenclature

Receptor	A₁	A_2A	A_2B	A₃
Receptor Code	2.1:ADO:	2.1:ADO:	2.1:ADO:	2.1:ADO:
Previous names	R_i	A_2a, R_s	A_2b, R_s
Structural information	7TM; human 326 aa, P30542, chr 1q32.1, rat 326 aa,P25099, mouse 326 aa	7TM; human 410 aa, P29274, chr 22g11.2, rat 409 aa, P30543, mouse 409 aa, UO5672	7TM; human 328 aa, P29275, chr 17p11.2–12; rat 332 aa, P29276 mouse 332 aa, UO5673	7TM; human 318 aa, P33765, chr 1p21–13, rat 320 aa P28647 (see comments), mouse 320 aa, AF069778
Selective agonists	CPA, CCPA, CHA	CGS 21680, HENECA, CV-1808, CV-1674, ATL146e	None	Cl-IB-MECA
Selective antagonists	DPCPX^1-a8-cyclopentyl-theophylline, WRC0571	selective: SCH 58261^1-b ^1-c moderately selective: ZM241385,^1-a KF 17387, CSC	MRS1754,^1-d enprofylline, alloxazine (historical)	MRS 1220,^1-eMRE 3008-F20,^1-e MRS 1191; MRS 1523
Tissue functions	Bradycardia; inhibition of lipolysis; reduced glomerular filtration; tubero-glomerular feedback, antinociception; reduction of sympathetic and parasympathetic activity; presynaptic inhibition; neuronal hyperpolarization; ischemic preconditioning	Regulation of sensorimotor integration in basal ganglia; inhibition of platelet aggregation and polymorphonuclear leukocytes; vasodilatation, protection against ischemic damage, stimulation of sensory nerve activity	Relaxation of smooth muscle in vasculature and intestine; inhibition of monocyte and macrophage function, stimulation of mast cell mediator release (some species)	Enhancement of mediator release from mast cells (some species). Preconditioning (some species)
Phenotypes	Tissue functions above confirmed in knockout mouse	Tissue functions above confirmed in knockout mouse		Tissue functions above confirmed in knockout mouse
Comments	Also cloned from dog,^1-fcow,^1-grabbit^1-i ^1-j	Also cloned from e.g. dog,^1-h guinea pig.^1-k Variations in structure among humans		Alternative splicing in rat can yield product with 337 aa.^1-l Also cloned from sheep^1-m 317 aa, rabbit^1-j 320 aa

↵1-a DPCPX and ZM241385 also have nanomolar affinity for the adenosine A_2B receptor.
↵1-b Dionisotti et al., 1997.
↵1-c Ongini et al., 1999.
↵1-d Kim et al., 2000.
↵1-e Li et al., 1999;Baraldi et al., 2000b.
↵1-f Libert et al., 1989,1991.
↵1-g Tucker et al., 1992.
↵1-h Maenhaut et al., 1990.
↵1-i Bhattacharya et al., 1993.
↵1-j Hill et al., 1997.
↵1-k Meng et al., 1994.
↵1-l Sajjadi et al., 1996.
↵1-m Linden et al., 1993.

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Table 2

Mutational analysis of the adenosine A₁ with respect to ligand binding

Mutation^2-a	Species	Helix/position^2-b	Effect on Ligand Binding and Signal Transduction	Reference
G14T	H	1.37	Increased agonist affinity	Rivkees et al., 1999a
E16A/Q	H	1.39	Agonist affinity reduced 4- to 40-fold; little change in antagonist affinity	Barbhaiya et al., 1996
P25L	H	1.48	Modest reduction of agonist affinity	Rivkees et al., 1999a
I31C	H	1.54	No changes in radioligand binding	Rivkees et al., 1999a
C46A/S	H	2.41	No changes in radioligand binding	Scholl and Wells, 2000
S50A	H	2.45	No changes in radioligand binding	Barbhaiya et al., 1996
D55A	H	2.50	Increase in agonist affinity with no change in antagonist affinity; disrupted regulation of agonist binding by sodium ions	Barbhaiya et al., 1996
L65F	H	2.60	No changes in radioligand binding	Rivkees et al., 1999a
C80A/S	H	3.25	No detectable radioligand binding	Scholl and Wells, 2000
M82F	H	3.27	No changes in radioligand binding	Rivkees et al., 1999a
C85A	H	3.30	No changes in radioligand binding	Scholl and Wells, 2000
C85S			Agonist affinity reduced 4- to 13-fold; no change in antagonist affinity	Scholl and Wells, 2000
P86F	H	3.31	Substantial reduction of agonist binding	Rivkees et al., 1999a
V87A	H	3.32	No change in ligand affinity	Rivkees et al., 1999a
L88A	H	3.33	Substantial reduction of agonist binding, but also of N-0840 antagonist binding	Rivkees et al., 1999a
T91A	H	3.36	Substantial reduction of agonist binding, but also of N-0840 antagonist binding	Rivkees et al., 1999a
Q92A	H	3.37	Substantial reduction of agonist binding, but also of N-0840 antagonist binding	Rivkees et al., 1999a
S93A	H	3.38	No changes in radioligand binding	Barbhaiya et al., 1996
S94A	H	3.39	No detectable agonist or antagonist binding	Barbhaiya et al., 1996
S94T			Minor changes in ligand binding	Barbhaiya et al., 1996
A125K	H	4.43	No changes in radioligand binding	Rivkees et al., 1999a
C131A/S	H	4.49	No changes in radioligand binding	Scholl and Wells, 2000
S135A	H	4.53	No changes in radioligand binding	Barbhaiya et al., 1996
T141A	H	4.59	No changes in radioligand binding	Barbhaiya et al., 1996
F144L	H	4.62	No changes in radioligand binding	Rivkees et al., 1999a
C169A/S	H		No detectable radioligand binding	Scholl and Wells, 2000
H251L	B	6.52	Antagonist affinity reduced 4-fold; no change in agonist affinity	Olah et al., 1992
C255A/S	H	6.56	No changes in radioligand binding	Scholl and Wells, 2000
C260A/S	H		No changes in radioligand binding	Scholl and Wells, 2000
C263A/S	H		No changes in radioligand binding	Scholl and Wells, 2000
I270M M270I	B, C	7.35	Amino acid in position 270 contributes to canine/bovine A₁ AR binding selectivity	Tucker et al., 1994
T277A	H	7.42	400-fold decrease in affinity of NECA with modest changes in affinity for R-PIA andS-PIA (intact cells); substantial decrease in affinity of all agonists (membranes); no change in antagonist affinity	Townsend-Nicholson and Schofield, 1994;Dalpiaz et al., 1998
T277S			Modest decrease in agonist affinity; no change in antagonist affinity; nature of residue in position 277 also involved in canine/bovine A₁ AR binding specificity	Tucker et al., 1994; Townsend-Nicholson and Schofield, 1994
H278L	B	7.43	Negligible agonist and antagonist binding	Olah et al., 1992
C309A/S	H		No changes in radioligand binding	Scholl and Wells, 2000

The results were obtained from site-directed mutagenesis studies of the A₁ AR (species; H, human; B, bovine; C, canine).
↵2-a Amino acids are represented in single-letter code with position number shown. The first amino acid is that of the wild-type receptor, with the second residue being that used for substitution.
↵2-b Position on helix, using notation of van Rhee and Jacobson (1996).

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Table 3

Mutational analysis of the human A_2A AR with respect to ligand binding

Mutation^3-a	Helix/Position^3-b	Effect on Ligand Binding and Signal Transduction	Reference
E13Q	1.39	Slight reduction of agonist, but not antagonist, affinity	IJzerman et al., 1996
T88A/S/R	3.36	Substantial decrease in agonist, but not antagonist, affinity	Jiang et al., 1996
Q89A	3.37	Slight increase in agonist and antagonist affinity	Jiang et al., 1996
Q89N/S/L		Marginal changes in ligand binding
Q89H/R		Antagonist binding affected
S90A	3.38	Marginal changes in ligand binding	Jiang et al., 1996
S91A	3.39	Marginal changes in ligand binding	Jiang et al., 1996
E151A/Q/D		Loss of agonist and antagonist radioligand binding	Jiang et al., 1996
E169A		∼1000-fold decrease in agonist potency	Kim et al., 1996
E169A		Gain inN ⁶-substituted agonist affinity	Kim et al., 1996
D170K		No change in (radio)ligand binding	Kim et al., 1996
P173R
F180A	5.41	Minor changes in ligand binding	Kim et al., 1995
N181S	5.42	Modest reduction of agonist binding	Kim et al., 1995
F182A	5.43	Loss of agonist and antagonist radioligand binding	Kim et al., 1995
F182Y		Modest reduction of agonist binding	Kim et al., 1995
F182W		Modest reduction of agonist binding	Kim et al., 1995
H250A	6.52	Loss of agonist and antagonist radioligand binding; no agonist activity in functional assays	Kim et al., 1995
H250F/Y		Modest reduction of agonist binding; no effect on antagonist binding	Kim et al., 1995
N253A	6.55	Loss of agonist and antagonist radioligand binding	Kim et al., 1995
C254A	6.56	Minor changes in ligand binding	Kim et al., 1995
F257A	6.59	Loss of agonist and antagonist radioligand binding	Kim et al., 1995
C262G	6.64	No change in radioligand binding	Kim et al., 1996
I274A	7.39	Loss of agonist and antagonist radioligand binding; ∼30-fold decrease in agonist potency	Kim et al., 1995
S277A	7.42	Substantial decrease in agonist affinity and potency, but antagonist radioligand binding not altered	Kim et al., 1995
S277T/C/N		Marginal changes in ligand binding	Jiang et al., 1996
H278A	7.43	Loss of agonist and antagonist radioligand binding; ∼300-fold decrease in agonist potency	Kim et al., 1995
H278Y		Modest reduction of agonist binding; no effect on antagonist binding	Gao et al., 2000
S281A	7.46	Loss of agonist and antagonist radioligand binding; no agonist activity in functional assays	Kim et al., 1995
S281T		Enhanced affinity for most agonists	Kim et al., 1995
S281N		Marginal changes in ligand binding	Gao et al., 2000

↵3-a Amino acids are represented in single-letter code with position number shown. The first amino acid is that of the wild-type receptor, with the second and further residues those used for substitution.
↵3-b Position on helix, using notation of van Rhee and Jacobson (1996).

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Table 4

Mutational analysis of the human A_2B AR with respect to ligand binding

Mutation^4-a	Helix/Position^4-b	Effect on Ligand Binding and Signal Transduction	Reference
V11I	1.36	No changes in (radio)ligand binding	Beukers et al., 2000
A12T	1.37	No changes in (radio)ligand binding	Beukers et al., 2000
L58V	2.55	No changes in (radio)ligand binding	Beukers et al., 2000
F59L	2.56	No specific radioligand binding and no cAMP production	Beukers et al., 2000
N273Y	7.36	Up to 60-fold increase in affinity of 2-substituted adenosines	Beukers et al., 2000

↵4-a Amino acids are represented in single-letter code with position number shown. The first amino acid is that of the wild-type receptor, and the second is the one used for substitution, based on the corresponding amino acid in the human A_2A receptor.
↵4-b Position on helix, using notation of van Rhee and Jacobson (1996).

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Table 5

Summary of the distribution of adenosine receptors

A₁ Receptor	A_2AReceptor	A_2B Receptor	A₃ Receptor
High expression	High expression	High expression	High expression
Brain (cortex, cerebellum, hippocampus). Dorsal horn of spinal cord. Eye, adrenal gland, atria	Spleen, thymus, leukocytes (both lymphocytes and granulocytes), blood platelets. Striatopallidal GABAergic neurons (in caudate-putamen, nucleus accumbens, tuberculum olfactorium), olfactory bulb	Cecum, colon, bladder	Testis (rat), mast cells (rat)
Intermediate levels	Intermediate levels	Intermediate levels	Intermediate levels
Other brain regions. Skeletal muscle, liver, kidney, adipose tissue, salivary glands, esophagus, colon, antrum, testis	Heart, lung, blood vessels	Lung, blood vessels, eye, median eminence, mast cells	Cerebellum (human?), hippocampus (human?), lung, spleen (sheep), pineal
Low levels	Low levels	Low levels	Low levels
Lung (but probably higher in bronchi), pancreas	Other brain regions	Adipose tissue, adrenal gland, brain, kidney, liver, ovary, pituitary gland	Thyroid, most of brain, adrenal gland, spleen (human), liver, kidney, heart, intestine, testis (human)

Data where there is correspondence between mRNA distribution and receptor distribution are given in bold. Data based mainly or exclusively on distribution of mRNA are given in ordinary letters. Ambiguous data (including major species differences) are given in italics.

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Table 6

Pharmacological tools used for classification of adenosine receptors

Abbreviations	Chemical Names
AB-MECA	4-aminobenzyl-5′-N-methylcarboxamidoadenosine
ATL146e	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
BW-A1433	1,3-dipropyl-8-(4-acrylate)phenylxanthine
CGS 15943	5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c]quinazoline
CGS 21680	2-[p-(2-carbonyl-ethyl)-phenylethylamino]-5′-N-ethylcarboxamidoadenosine
CP 66713	4-amino-8-chloro-1-phenyl-[1,2,4]-triazolo-[4,3-a] quinoxaline
CPA	N ⁶-cyclopentyladenosine
CPX	8-cyclopentyl-1,3-dipropylxanthine (see also DPCPX)
CSC	8-(3-chlorostyryl)caffeine
CV-1808	2-phenylaminoadenosine
DPCPX	1,3-dipropyl-8-cyclopentylxanthine
HENECA	2-hex-1-ynyl-5′-N-ethylcarboxamidoadenosine
I-ABA	N ⁶-(4-amino-3-iodobenzyl)adenosine
I-ABOPX	3-(3-iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine
IB-MECA	N ⁶-(3-iodobenzyl)adenosine-5′-N-methyluronamide
KF 17837	1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine
KW 6002	(E)-8-[2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-7-methyl-1h-purine-2,6-dione
MRE 3008-F20	5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
MRS1191	3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate
MRS1220	9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-c]quinazoline
MRS1523	2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate
MRS1754	N-(4-cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]acetamide
NECA	5′-N-ethyl-carboxamidoadenosine
PAPA-APEC	2-(4-[2-[(4-aminophenyl)methylcarbonyl]ethyl]phenyl)ethylamino-5′-N-ethylcarboxamidoadenosine
PD 81723	(2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)-phenyl]-methanone
R-PIA	R-N ⁶-(phenylisopropyl)-adenosine
SCH 58261	5-amino-2-(2-furyl)-7-phenylethyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
S-PIA	S-N ⁶-(phenylisopropyl)-adenosine
VUF-8504	4-methoxy-N-[2-(2-pyridinyl)quinazolin-4-yl]benzamide
XAC	xanthine amine congener; 8-[4-[[[[(2-aminoethyl)amino]-carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine
ZM241385	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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Table 7

Binding affinity of agonists and antagonists at human adenosine receptor subtypes (K _i values with 95% confidence intervals or ± S.E.M. in parentheses)

	A₁	A_2A	A_2B	A₃	Reference
Agonists with unmodified ribose
R-PIA	2.0 (1–4.2)	860 (480–1,540)		16 (9.3–29)	—^7-a
			33,700 (±6,800)		—^7-c
			3,800 (±1,700)		—^7-e
S-PIA	75 (42–134)	7,800 (7,000–8,640)		45 (33–61)	—^7-a
			62,800 (±21,600)		—^7-c
CPA	2.3 (1.5–3.4)	790 (470–1,360)		43 (30–61)	—^7-a
			34,400 (±11,100)		—^7-c
			21,000 (±4,300)		—^7-e
CCPA	0.8 (0.55–1.25)	2,300 (2,000–2,700)		42 (32–56)	—^7-a
			40,100 (±16,400)		—^7-c
2-Cl-adenosine	1.39 (1.28–1.51)	180 (150–220)		19 (14–28)	—^7-i
Agonists with 5′-modified ribose
NECA	14 (6.4–29)	20^7-150 (12–35)		6.2^7-150 (3.5–11)	—^7-a
			330 (±60)		—^7-c
			360 (±120)		—^7-e
CGS 21680	290 (230–360)	27 (12–59)		67 (50–90)	—^7-a
			361,000 (±21,000)		—^7-c
HENECA	60 (50–72)	6.4 (3.8–11)		2.4 (2.0–2.9)	—^7-b
PENECA	560 (480–650)	620 (300–1,300)		6.2 (5.1–7.5)	—^7-b
PHPNECA	2.7 (1.7–7.1)	3.1 (2.4–3.9)		0.42 (0.17–1.0)	—^7-b
AB-MECA	1,500 (1,300–1,800)	3,600 (2,700–4,700)		22 (20–24)	—^7-a
IB-MECA	3.7 (1.8–7.7)	2,500 (1,900–3,400)		1.2 (0.96–1.5)	—^7-a
			54,000 (±5,600)		—^7-c
IAB-MECA	8.5 (4.8–15)	470 (300–740)		0.64 (0.58–0.70)	—^7-a
Cl-IB-MECA	115 (114–116)	2,100 (1,700–2,500)		11 (9.4–13)	—^7-b
Antagonists: xanthines
DPCPX	3.9^7-150 (3.5–4.2)	129 (35–260)		4,000 (2,600–6,000)	—^7-a
			50 (±3.7)		—^7-c
			51 (±6.1)		—^7-e
XAC	29 (24–35)	1 (0.58–1.7)		92 (64–130)	—^7-a
			7.3 (±2.8)		—^7-c
			12 (±4.6)		—^7-e
MRS1754	400 (±190)	500 (±11)	2.0 (±0.31)	570 (±180)	—^7-f
MSX-2	2,500 (1,700–3,600)	5.0 (±0.6)		>10,000	—^7-h
Theophylline	6,800 (4,100–11,000)	1,700 (1,000–2,900)		86,000 (74,000–101,000)	—^7-a
Antagonists: non-xanthines
CGS 15943	3.5 (1.7–7.3)	4.2 (2.6–6.6)		51 (43–60)	—^7-a
			16 (±3.6)		—^7-e
SCH 58261	290 (210–410)	0.6 (0.5–0.7)		>10,000	—^7-d
ZM 241385	260 (190–390)	0.8 (0.7–1.0)		>10,000	—^7-d
			32 (±6)		—^7-c
MRE 3008F20	1,100 (±1,100)	140 (±15)	2,100 (±300)	0.29 (±0.03)	—^7-g

↵7-150 Values are from saturation experiments.
↵7-a Klotz et al., 1998, transfected CHO cells; radioligands [³H]CCPA (A₁), [³H]NECA (A_2A and A₃).
↵7-b Klotz et al., 1999, transfected CHO cells; radioligands [³H]CCPA (A₁), [³H]NECA (A_2A and A₃).
↵7-c Linden et al., 1999, transfected HEK 293 cells; radioligand ¹²⁵I-ABOPX.
↵7-d Ongini et al., 1999, transfected CHO cells (A₁ and A_2A) or HEK 293 cells (A_2A and A₃); radioligands [³H]DPCPX (A₁), [³H]SCH 58261 (A_2A), ¹²⁵I-AB-MECA (A₃).
↵7-e Ji and Jacobson, 1999, transfected HEK 293 cells; radioligand [³H]ZM 241685.
↵7-f Kim et al., 2000, transfected HEK 293 cells; radioligands ¹²⁵I-ABA (A₁), ¹²⁵I-ZM 241685 (A_2A),¹²⁵I-ABOPX (A_2B), ¹²⁵I-AB-MECA (A₃).
↵7-g Varani et al., 2000, transfected CHO cells; radioligands [³H]DPCPX (A₁ and A_2B), [³H]SCH 58261 (A_2A), ¹²⁵I-AB-MECA (A₃).
↵7-h Sauer et al., 2000, transfected CHO cells; radioligand [³H]CHA (A₁), [³H]CGS 21680 (A_2A), [³H]NECA (A₃).
↵7-i K.-N. Klotz and S. Kachler, unpublished, transfected CHO cells; radioligand [³H]NECA.

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Table 8

Binding affinity of agonists and antagonists at rat adenosine receptor subtypes (K _i values with 95% confidence intervals or ±S.E.M. in parentheses)

	A₁	A_2A	A₃	Reference
Agonists with unmodified ribose
R-PIA	1.2 (±0.16)	124 (±9)		—^8-a
	1.3 (1.1–1.6)	730 (690–770)		—^8-b
	0.51			—^8-c
			220 (±43)	—^8-d
			160 (±52)	—^8-e
S-PIA	49 (±2.4)	1,800 (±380)		—^8-a
	29			—^8-f
			920 (±310)	—^8-e
CPA	0.59 (±0.02)	460 (±15)		—^8-a
	0.8 (0.6–1.0)	2,000 (1,400–2,900)		—^8-b
			240 (±36)	—^8-e
CCPA	0.4 (0.2–0.7)	3,900 (2,500–4,700)		—^8-b
	0.23			—^8-c
			240 (±71)	—^8-e
ADAC	0.85 (±0.35)			—^8-w
2-Cl-adenosine	9.3 (±0.58)	63 (±7.5)		—^8-a
			1,900 (±900)	—^8-e
DPMA	140 (±23)	4.4 (±0.2)		—^8-u
			3,600 (±1,700)	—^8-e
(S)-ENBA	0.3 (±0.02)	1,400 (±150)		—^8-v
Agonists with 5′-modified ribose
NECA	6.3 (±0.52)	10 (±0.5)		—^8-a
	11 (7.0–17)	22 (20–25)		—^8-f
	3.7			—^8-c
			260 (±36)	—^8-d
CGS 21680	3100 (±470)	22 (±4.3)		—^8-g
			580 (±32)	—^8-e
HENECA	136 (95–195)	3.8 (1.5–9.9)		—^8-f
PENECA	698 (611–798)	120 (112–128)		—^8-h
PHPNECA	2.5 (2.2–2.9)	0.9 (0.7–1.3)		—^8-i
AB-MECA	430 (±45)	1,600 (±180)	14 (±3)	—^8-j
IB-MECA	54 (±5)	56 (±8)	1.1 (±0.3)	—^8-j
IAB-MECA	18 (±5)	200 (±84)	1.3 (±0.18)	—^8-j
Cl-IB-MECA	820 (±570)	470 (±370)	0.33 (±0.08)	—^8-k
Antagonists: xanthines
DPCPX	0.3	340		—^8-l
	0.18^8-150 (0.16–0.20)			—^8-l
			>10,000	—^8-e
XAC	2.8 (1.9–4.2)			—^8-m
	3.5	24		—^8-l
	4	50		—^8-n
			>100,000	—^8-o
MRS 1754	17 (±3.6)	610 (±290)		—^8-o
MSX-2	900 (±10)	8 (±3)		—^8-p
Theophylline	11,000	32,000		—^8-b
			>100,000	—^8-o
Antagonists: non-xanthines
CGS 15943	21 (±3.5)	3.3 (±1.8)		—^8-q
	22	3		—^8-n
	6.4 (6.2–6.6)	1.2 (1.1–1.3)		—^8-r
			>100,000	—^8-o
SCH 58261	120 (100–140)	2.3 (2.0–2.7)		—^8-r
ZM 241385	2,000 (1,500–2,700)	0.30 (0.10–0.95)	150,000 (87,000–210,000)	—^8-s
MRE 3008F20	>10,000	2,000 (±220)	>10,000	—^8-t

↵8-150 Data from saturation experiments; where confidence limits are missing, they are within 0.15 log units.
↵8-a Bruns et al., 1986; brain membranes (A₁), striatum (A_2A); radioligands [³H]CHA (A₁), [³H]NECA (A_2A).
↵8-b Lohse et al., 1988; brain membranes (A₁), striatum (A_2A); radioligands [³H]PIA (A₁), [³H]NECA (A_2A).
↵8-c Klotz et al., 1991; brain membranes; radioligand [³H]DPCPX.
↵8-d Olah et al., 1994; transfected CHO cells; radioligand ¹²⁵I-AB-MECA.
↵8-e van Galen et al., 1994; transfected CHO cells; radioligand¹²⁵I-APNEA.
↵8-f Cristalli et al., 1992; brain membranes (A₁), striatum (A_2A); radioligands [³H]DPCPX (A₁), [³H]NECA (A_2A).
↵8-g Hutchison et al., 1989; rat brain; radioligands [³H]CHA (A₁), [³H]NECA (A_2A). Given are IC₅₀ values; based on the experimental conditionsK _i values should be about 0.5–0.7 and 0.9 times the IC₅₀ values for A₁ and A_2A, respectively.
↵8-h Cristalli et al., 1995; brain membranes (A₁), striatum (A_2A); radioligands [³H]CHA (A₁), [³H]CGS 21680 (A_2A).
↵8-i Camaioni et al., 1997; brain membranes (A₁), striatum (A_2A); radioligands [³H]CHA (A₁), [³H]CGS 21680 (A_2A).
↵8-j Gallo-Rodriguez et al., 1994; rat brain (A₁), rat striatum (A_2A), transfected CHO cells (A₃); radioligand [³H]PIA (A₁), [³H]CGS 21680 (A_2A), ¹²⁵I-AB-MECA (A₃).
↵8-k Kim et al., 1994; rat brain (A₁), rat striatum (A_2A), transfected CHO cells (A₃); radioligand [³H]PIA (A₁), [³H]CGS 21680 (A_2A),¹²⁵I-AB-MECA (A₃).
↵8-l Lohse et al., 1987; brain membranes (A₁), striatum (A_2A); radioligands [³H]PIA (A₁), [³H]NECA (A_2A).
↵8-m Jacobson et al., 1986; rat brain, radioligand [³H]XAC.
↵8-n Jarvis et al., 1989; rat brain; radioligands [³H]CHA (A₁), [³H]CGS 21680 (A_2A).
↵8-o Kim et al., 2000; transfected HEK 293 cells (A₁), rat striatum (A_2A); radioligands [³H]PIA (A₁), [³H]CGS 21680 (A_2A).
↵8-p Sauer et al., 2000; brain cortex (A₁), striatum (A_2A); radioligand [³H]CHA (A₁), [³H]CGS 21680 (A_2A).
↵8-q Williams et al., 1987; brain (A₁), striatum (A_2A); radioligands [³H]CHA (A₁), [³H]NECA (A_2A). Given are IC₅₀values; based on the experimental conditions K _ivalues should be about 0.5–0.7 and 0.9 times the IC₅₀values for A₁ and A_2A, respectively.
↵8-r Baraldi et al., 1994; rat brain (A₁), rat striatum (A_2A); radioligand [³H]CHA (A₁), [³H]CGS 21680 (A_2A).
↵8-s Poucher et al., 1995; brain cortex (A₁), PC 12 cells (A_2A), transfected CHO cells (A₃); radioligands [³H]PIA (A₁), [³H]NECA (A_2A) ¹²⁵I-AB-MECA (A₃). Given are IC₅₀ values; based on the experimental conditionsK _i values should be about 0.1, 0.2, and 0.5 times the IC₅₀ values for A₁, A_2A, and A₃, respectively.
↵8-t Varani et al., 2000; brain cortex (A₁), striatum (A_2A), transfected CHO cells (A₃); radioligands [³H]DPCPX (A₁), [³H]SCH 58261 (A_2A),¹²⁵I-AB-MECA (A₃).
↵8-u Bridges et al., 1988; brain (A₁), striatum (A_2A); radioligand [³H]CHA (A₁), [³H]NECA (A_2A); DPMA or PD 125944 is compound 16 in this paper.
↵8-v Trivedi et al., 1989; brain (A₁), striatum (A_2A); radioligand [³H]CHA (A₁), [³H]NECA (A_2A).
↵8-w Jacobson et al., 1987; brain (A₁), radioligand [³H]PIA (A₁).

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Table 9

G protein coupling of the four adenosine receptor subtypes

Adenosine Receptor Subtype	G Protein	Effects of G Protein Coupling	Cellular System	Reference
A₁	G_i1/2/3	↓ cAMP ↑ IP3/DAG (PLC) ↑ Arachidonate (PLA2)	General, CHO cells^9-a	Freissmuth et al., 1991; Akbar et al., 1994; Freund et al., 1994; Jockers et al., 1994;Gerwins and Fredholm, 1995a,b
		↑ PEtOH (PLD)	DDT₁MF-2
	G_o			Jockers et al., 1994;Matovcik et al., 1994
A_2A	G_s	↑ cAMP	General	Olah, 1997
	G_olf	↑ cAMP		Kull et al., 2000a; Corvol et al., 2001
	G_15/16	↑ IP₃	COS-7^9-a	Offermanns and Simon, 1995
A_2B	G_s	↑ cAMP	General	Pierce et al., 1992
	G_q/11	↑ IP3/DAG (PLC)	HMC-1, HEK 293^9-a	Gao et al., 1999; Linden et al., 1999 ^9-b
A₃	G_i2,3	↓ cAMP	General, CHO cells^9-a	Palmer et al., 1995
	G_q/11	↑ IP3/DAG (PLC)	CHO cells^9-a	Palmer et al., 1995