International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

Bertil B. Fredholm; Adriaan P. IJzerman; Kenneth A. Jacobson; Joel Linden; Christa E. Müller

doi:10.1124/pr.110.003285

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Fig. 1.
Left, crystal structure of the adenosine A_2A receptor. Brown, α-helical elements; dark blue, ZM241385; yellow, disulfide bridges; pink, extracellular domain; red, stearic acid molecules; and light blue, intracellular domain. Membrane boundaries are represented as ellipsoids. Right, ligand binding site of the adenosine A_2A receptor. Brown, four transmembrane domains (helices 3, 5, 6, and 7); dark blue, ZM241385; blue spheres, explicit water molecules; pink, extracellular elements; yellow, disulfide bridges; and atom-coded colors, amino acid side chains involved in ligand binding.
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Fig. 2.
Nonselective and A₁-selective agonists.
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Fig. 3.
A_2A-selective agonists.
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Fig. 4.
A_2B-selective agonists.
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Fig. 5.
A₃-selective agonists.
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Fig. 6.
Nonselective and A₁-selective antagonists.
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Fig. 7.
A_2A-selective antagonists.
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Fig. 8.
A_2B- selective antagonists.
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Fig. 9.
A₃-selective antagonists.
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Fig. 10.
Selected allosteric enhancers of action of agonist at the A₁ adenosine receptor (A) and at the A_2A receptor (B).
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Fig. 11.
Bivalent ligand bridging orthosteric and allosteric site on the human A₁ adenosine receptor.
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Fig. 12.
Structures of pyridinylisoquinoline and imidizoquinolinamine derivatives that act as PAMs of of the human A₃ adenosine receptor and structure of 2-AG, which acts as a NAM of the A₃ receptor.

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TABLE 1

Some genetically modified animals useful to delineate adenosine receptor functions

Gene Targeted	Comment	References
AdoRA1	Major portion of coding exon 2 + ∼5 kb adjacent 3′ genomic seq; not lethal.	Johansson et al., 2001
	3′ portion of coding exon 1 + intron 5′ portion of coding exon 2, not lethal	Sun et al., 2001
AdoRA2A	Entire coding exon 2, not lethal	Ledent et al., 1997
	3′ portion of coding exon 2 ∼1.0 kb immediate intron seq, not lethal	Chen et al., 1999, 2001a
AdoRA2B	Replacement of exon 1 of the A_2BAR with a reporter construct containing the β-gal gene; not lethal.	Yang et al., 2006
	Replacement of part of the intron and the entirety of exon 2 (amino acids 113–332) with a marker gene; not lethal.	Hua et al., 2007b
AdoRA3	Entire coding exon 1 + 7.5 kb immediate intron seq; not lethal	Salvatore et al., 2000
Adenosine kinase	In frame insertion at exon amino acid Gly169-Thr225; die at P4	Boison et al., 2002
Adenosine deaminase	In frame insertion at exon 5; perinatal death Die at 3 weeks after trophoblast rescue	Blackburn et al., 1998
CD39	Part of exon 1; not lethal.	Enjyoji et al., 1999
CD73	Entire exon 3 + intronic sequences; not lethal.	Thompson et al., 2004
	Entire exon 2; not lethal.	Koszalka et al., 2004

kb, kilobase(s).

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TABLE 2

Selected effects mediated by adenosine via the four adenosine receptors

For this table we have predominantly used data from genetically modified organisms.

Receptor	Effect	Physiology/Pathophysiology	Evidence for Adaptation	Reference
A₁	Decreased renal blood flow, Tubuloglomerular feedback	Phys	No	Brown et al., 2001; Sun et al., 2001
	Inhibition of lipolysis	Phys	No	Johansson et al., 2008
	Vasoconstriction	?	?	Tawfik et al., 2005; Wang et al., 2010
	Inhibition of neurotransmitter release	Extreme phys	No?	Johansson et al., 2001
	Inhibition of insulin/glucagon release	Phys	No	Johansson et al., 2007a
	Reduced heart rate	Phys	No?	Yang et al., 2007
	Osteoclast activation, bone resorption	Phys?	No?	Kara et al., 2010a,b
	Sleep	Phys	Yes	Stenberg et al., 2003; Oishi et al., 2008
				Goldman et al. 2010
	Acupuncture	Extreme phys?	?
	Prevention of epilepsy	Path	?	Fedele et al. 2006; Li et al. 2007; Kochanek et al 2006
				Hua et al., 2007a
	Bronchoconstriction	Path	?
	Analgesia	Extreme phys	No	Johansson et al., 2001; Wu et al., 2005
	Preconditioning	Path	No	Schulte et al., 2004; Lankford et al., 2006
				Wendler et al. 2007
	Tolerance to hypoxia	Path	No?
A_2A	Wakefulness, locomotion	Phys	No	Ledent et al., 1997; El Yacoubi et al., 2000; Chen et al., 2000; Huang et al., 2005
	Neurodegeneration (including Parkinson's disease and Alzheimer's disease)	Path	No	Chen et al., 1999, 2001b, 2007
	Immunosuppression	Extreme/Path	No?	Ohta and Sitkovsky, 2001; Lappas et al., 2005; Ohta et al., 2007
	Vasodilatation/hypotension	Phys/Extreme	No?	Ledent et al., 1997
	Coronary vasodilatation	Phys/Extreme	Yes?	Morrison et al., 2002
	Inhibition of platelet aggregation	Extreme	No?	Ledent et al., 1997
	Angiogenesis	Extreme	No?	Montesinos et al., 2002
A_2B	Vascular integrity	Phys/Extreme	No	Yang et al., 2006, 2008
	Preconditioning	Extreme	No	Eckle et al., 2007
A₃	Increased mast cell activation	Extreme/Path	No?	Salvatore et al., 2000; Tilley et al., 2000
	Airway contraction	Path	No?	Hua et al., 2008
	Inflammatory pain	Extreme/Path	No?	Wu et al., 2002
	White cell chemotaxis	Extreme/Path	No?	Chen et al., 2006

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TABLE 3

Adenosine receptor affinities of agonists

Most data for A_2B are from functional studies.

		K_i
		A₁	A_2A	A_2B	A₃
		nM
Nonselective agonists
1	Adenosine^{^a}	∼100 (h)^{^b}	310 (h)^{^b}	15,000 (h)^{^b}	290 (h)^{^b}
		73 (r)^{^b}	150 (r)^{^b}	5100 (r)^{^b}	6500 (r)^{^b}
2	2-Chloro-adenosine	6.7 (r)^{^c}	76 (r)^{^c}	24,000 (h)^{^d}	1890 (r)^{^e}
3	NECA	14 (h)^{^b}	20 (h)^{^b}	140 (h)^{^b}	25 (h)^{^b}
		5.1 (r)^{^f}	9.7 (r)^{^f}	1890 (h)^{^g}	113 (r)^{^f}
				1900 (m)^{^f}
A₁-selective agonists
4	R-PIA	2.04 (h)^{^h}	220 (r)^{^c}	150,000 (h)^{^d}	33 (h)^{^u}
		1.2 (r)^{^c}		19,000 (m)^{^j}	158 (r)^{^e}
5	GW493838	N.D.	N.D.	N.D.	N.D.
6	CHA	0.85 (r)^{^c}	460 (r)^{^c}	160,000 (h)^{^d}	1025 (h)^{^k}
					176 (r)^{^e}
7	CPA	2.3 (h)^{^l}	794 (h)^{^l}	18,600 (h)^{^l}	72 (h)^{^l}
8	CCPA	0.83 (h)^{^l}	2270 (h)^{^l}	18,800 (h)^{^l}	38 (h)^{^l}
		1.3 (r)^{^m}	950 (r)^{^m}		237 (r)^{^m}
		0.1 (rb)^{^m}			37.7 (rb)^{^m}
9	TCPA	2.8 (h)^ⁿ	210 (h)^ⁿ	>10,000 (h)^ⁿ	600 (h)^ⁿ
10	2′-Me-CCPA	1.8 (c)^{^o}	3900 (c)^{^o}	N.D.	5000 (r)^{^o}
11	Selodenoson (DTI-0009)	N.D.	N.D.	N.D.	N.D.
12	GR79236	3.1 (r)^{^l}	1300 (h)^{^l}	N.D.	N.D.
13	Tecadenoson	6.5 (p)^{^l}	2315 (h)^{^l}	N.D.	N.D.
14	GS9667 (CVT-3619)	55 (h)^{^p}	>10,000 (h)^{^p}	>50,000 (h)^{^p}	>1000 (h)^{^p}
15	Capadenoson (BAY 68-4986)	N.D.	N.D.	N.D.	N.D.
A_2A-selective agonists
16	CGS21680	289 (h)^{^l}	27 (h)^{^l}	>10,000 (h)^{^l}	67 (h)^{^l}
		1800 (r)^{^m}	19 (r)^{^m}	>10,000 (r)^{^m}	584 (r)^{^m}
		120 (rb)^{^m}			673 (rb)^{^m}
17	Apadenoson (ATL-146e)	77 (h)^{^l}	0.5 (h)^{^l}	N.D.	45 (h)^{^l}
18	ATL-313	N.D.	N.D.	N.D.	N.D.
19	UK-432097	N.D.	4 (h)	N.D.	N.D.
20	Sonedenoson (MRE-0094)	N.D.	N.D.	N.D.	N.D.
21	Binodenoson (WRC-0470)	48,000 (h)^{^l}	270 (h)^{^l}	430,000 (h)^{^l}	903 (h)^{^l}
22	Regadenoson (CV-3146)	>10,000 (h)^{^l}	290 (h)^{^l}	>10,000 (h)^{^l}	>10,000 (h)^{^l}
A_2B-selective agonists
23	A_2B agonist	1050 (h)^{^q}	1550 (h)^{^q}	82 (h)^{^q}	>5000 (h)^{^q}
24	BAY 60-6583	>10,000 (h)^{^a,^r}	>10,000 (h)^{^a,^r}	3–10 (h)^{^r}	>10,000 (h)^{^a,^r}
				330 (m)^{^s}
				750 (d)^{^s}
				340 (rb)^{^s}
A₃-selective agonist
25	IB-MECA (CF101)	51 (h)^{^l}	2900 (h)^{^l}	11,000 (h)^{^l}	1.8 (h)^{^l}
26	Cl-IB-MECA	220 (h)^{^l}	5360 (h)^{^l}	>10,000 (h)^{^m}	1.4 (h)^{^l}
	CF102	280 (r)^{^m}	470 (r)^{^m}	>10,000 (m)^{^m}	0.33 (r)^{^m}
		35 (m)^{^m}	∼10,000 (m)^{^m}		0.18 (m)^{^m}
27	CP608,039	7300 (h)^{^t}	N.D.	N.D.	5.8 (h)^{^t}
		1750 (rb)^{^t}			83 (rb)^{^t}
28	HEMADO	330 (h)^{^u}	1200 (h)^{^u}	>30,000 (h)^{^u}	1.10 (h)^{^u}
29	2-Phenylethynyl-adenosine derivative	32,800 (h)^{^v}	41,700 (h)^{^v}	>30,000 (h)^{^v}	0.44 (h)^{^v}
30	MRS3558 (CF502)	260 (h)^{^l}	2330 (h)^{^l}	>10,000 (h)^{^l}	0.29 (h)^{^l}
		105 (r)^{^m}	1080 (r)^{^m}		1.0 (r)^{^m}
		15.8 (m)^{^m}	10,400 (m)^{^m}		1.49 (m)^{^m}
31	MRS5151	14,900 (h)^{^w}	∼10,000 (h)^{^w}	N.D.	2.38 (h)^{^w}
		10,500 (m)^{^w}	>10,000 (m)^{^w}		24.4 (m)^{^w}

h, human; c, cow; d, dog; m, mouse; p, pig; r, rat; rb, rabbit; R-PIA, (R)-N⁶-phenylisopropyladenosine; N.D., no data available; CHA, N⁶-cyclohexyladenosine; CCPA, 2-chloro-N⁶-cyclopentyladenosine; TCPA, N⁶-cyclopentyl-2-(3-phenylaminocarbonyltriazene-1-yl)adenosine; ATL-313, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-y nyl}piperidine-1-carboxylic acid methyl ester; CP608,039, (2S,3S,4R,5R)-3-amino-5-{6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide; HEMADO, 2-(1-hexynyl)-N-methyladenosine; MRS3558, (1′S,2′R,3′S,4′R,5′S)-4′-{2-chloro-6-[(3-chlorophenylmethyl)amino]purin-9-yl}-1-(methylaminocarbonyl)bicyclo[3.10.0]hexane-2,3-diol; MRS5151, (1′S,2′R,3′S,4′R,5′S)-4′-[6-(3-chlorobenzylamino)-2-(5-hydroxycarbonyl-1-pentynyl)-9-yl]-2′,3′-dihydroxybicyclo[3.10.0]hexane-1′-carboxylic acid N-methylamide.
↵a Data are from functional studies.
↵b Yan et al., 2003.
↵c Daly et al., 1993.
↵d Bruns, 1980.
↵e van Galen et al., 1994.
↵f Müller and Stein, 1996.
↵g Data from radioligand binding studies versus the antagonist radioligand [³H]PSB-603 (S. Hinz and C. E. Müller, unpublished data).
↵h Klotz et al., 1998.
↵u Salvatore et al., 1993.
↵j Brackett and Daly, 1994.
↵k Sajjadi et al., 1996.
↵l Jacobson and Gao, 2006.
↵m Liang et al., 2010.
↵n Beukers et al., 2003.
↵o Franchetti et al., 1998.
↵p Elzein and Zablocki, 2008.
↵q Baraldi et al., 2007.
↵r Kuno et al., 2007.
↵s Data from radioligand binding studies versus the antagonist radioligand [³H]MRS1754 (Auchampach et al., 2009).
↵t Tracey et al., 2003.
↵u Volpini et al., 2002; Klotz et al., 2007.
↵v Volpini et al., 2009.
↵w Melman et al., 2008.

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TABLE 4

Adenosine receptor affinities of antagonists

A few A_2B data are from functional (cAMP) studies.

		K_i
		A₁	A_2A	A_2B	A₃
		nM
Nonselective antagonists
32	Caffeine	10,700 (h)^{^a}	23,400 (h)^{^b}	33,800 (h)^{^c}	13,300 (h)^{^a}
		44,900 (h)^{^b}	9560 (h)^{^a}	10,400 (h)^{^d}	>100,000 (r)^{^e}
		41,000 (r)^{^f}	45,000 (r)^{^g}	20,500 (h)^{^h}
		44,000 (r)^{^g}	32,500 (r)^{^u}	30,000 (r)^{^j}
		47,000 (gp)^{^k}	48,000 (r)^{^a}	13,000 (m)^{^j}
		44,000 (c)^{^k}
33	Theophylline	6770 (h)^{^l}	1710 (h)^{^l}	9070 (h)^{^d}	22,300 (h)^{^a}
		14,000 (r)^{^m}	6700 (h)^{^a}	74,000 (h)^{^h} 15,100 (r)^{^d}	86,400 (h)^{^l}
		8740 (r)^{^a}	22,000 (r)^{^m}	5630 (m)^ⁿ	>100,000 (r)^{^e}
		7060 (gp)^{^o}	25,300 (r)^{^a}	11,000 (gp)^{^p}	85,000 (r)^{^q}
		4710 (rb)^{^o}		17,700 (rb)^ⁿ	>100,000 (d)^{^r}
		9050 (s)^{^o}		38,700 (d)^ⁿ
		6330 (c)^{^o}
34	CGS15943	3.5 (h)^{^s}	1.2 (h)^{^s}	32.4 (h)^ⁿ	35 (h)^{^s}
		6.4 (r)^{^s}		9.07 (m)^ⁿ
A₁-selective antagonists
35	DPCPX (CPX)	3.0 (h)^{^t}	129 (h)^{^l}	51 (h)^{^t}	795 (h)^{^u}
		0.50 (r)^{^t}	60 (h)^{^t}	63.8 (h)^{^d}	243 (h)^{^t}
		1.0 (r)^{^d}	157 (r)^{^u}	186 (r)^{^d}	509 (h)^{^r}
		0.18 (r)^{^o}	500 (r)^{^d}	200 (r)^{^p}	3960 (h)^{^l}
		1.06 (gp)^{^o}		86.2 (m)^ⁿ	>10,000 (r)^{^t}
		3.9 (gp)^{^k}		145 (gp)^{^p}	43,000 (r)^{^r}
		0.21 (rb)^{^o}		96.0 (rb)^ⁿ	708 (rb)^{^r}
		0.10 (s)^{^o}		147 (d)^ⁿ	115 (d)^{^c}
		0.05 (c)^{^o}		132 (d)^{^p}
		0.29 (c)^{^k}
		11.4 (d)^{^r}
36	CPFPX	1.26 (h)^{^v}	940 (h)^{^v}	nd^{^b}	N.D.
		0.63 (r)^{^v}	812 (r)^{^v}
		1.37(p)^{^v}
		0.18 (c)^{^v}
37	Rolofylline (KW-3902, NAX)	0.72 (h)^{^w}	108 (h)^{^w}	296 (h)^{^x}	4390 (h)^{^x}
		8.0 (h)^{^x}	673 (h)^{^x}
		0.19 (r)^{^y}	380 (r)^{^y}
		12.6 (r)^{^w}	510 (r)^{^w}
38	PSB-36	0.7 (h)^{^t}	980 (h)^{^t}	187 (h)^{^t}	2300 (h)^{^t}
		0.124 (r)^{^t}	552 (r)^{^t}		6500 (r)^{^t}
39	Toponafylline (BG-9928)	7.4 (h)^{^x}	6410 (h)^{^x}	90 (h)^{^x}	>10,000 (h)^{^x}
		3.9 (mk)^{^z}	943 (mk)^{^z}
		1.3 (r)^{^x}	2440 (r)^{^x}
		29 (d)^{^z}	4307 (d)^{^z}
40	FK-453	18 (h)^{^aa}	1300 (h)^{^aa}	980 (h)^{^aa}	>10,000 (h)^{^aa}
41	SLV320	1.00 (h)^{^bb}	398 (h)^{^bb}	3981 (h)^{^bb}	200 (h)^{^bb}
		2.51 (r)^{^bb}		501 (r)^{^bb}
42	LUF5981	0.90 (h)^{^cc}	194 (h)^{^cc}	>300 (h)^{^cc}	637 (h)^{^cc}
A_2A-selective antagonists
43	Istradefylline (KW6002)	841 (h)^{^dd}	12 (h)^{^ee}	>10,000 (h)^{^dd}	4470 (h)^{^dd}
		230 (r)^{^dd}	91.2 (h)^{^dd}
			2.2 (r)^{^ff}
			4.46 (r)^{^gg}
44	CSC (K_i MAO-B = 80.6 nM)^{^gg}	28,000 (r)^{^hh}	54 (r)^{^hh}	8200^ⁱⁱ	>10,000 (r)^{^e}
45	MSX-2	900 (r)^{^jj}	8.04 (r)^{^u}^,^{^jj}	>10,000 (h)^{^jj}	>10,000 (h)^{^jj}
		2500 (h)^{^jj}	5.38 (h)^{^jj}^,^{^kk}	2900 (h)^{^ll}
			14.5 (h)^{^jj}^,^{^mm}
46	SYN-115	N.D.	N.D.	N.D.	N.D.
47	BIIB014 (V2006)	68 (h)^ⁿⁿ	1.3 (h)^ⁿⁿ	63 (h)^ⁿⁿ	1005 (h)^ⁿⁿ
48	ZM-241385	774 (h)^{^aa}	1.6 (h)^{^aa}	75 (h)^{^aa}	743 (h)^{^aa}
49	ST-1535	71.8 (h)^{^oo}	6.6 (h)^{^oo}	352.3 (h)^{^oo}	>1000 (h)^{^oo}
50	SCH-58261	725 (h)^{^aa}	5.0 (h)^{^aa}	1110 (h)^{^aa}	1200 (h)^{^aa}
51	Preladenant (SCH-420814)	>1000 (h)^{^pp}	0.9 (h)^{^pp}	>1000 (h)^{^pp}	>1000 (h)^{^pp}
52	SCH-442416	1110 (h)^{^aa}	4.1 (h)^{^qq}	>10,000 (h)^{^aa}	>10,000 (h)^{^aa}
A_2B-selective antagonists
53	MRS1754	403 (h)^{^rr}	503 (h)^{^rr}	1.97 (h)^{^rr}	570 (h)^{^rr}
		16.8 (r)^{^rr}	612 (r)^{^rr}	12.8 (r)^{^rr}
				16.6 (r)^{^p}
				3.39 (m)^ⁿ
				9.12 (gp)^{^p}
				1.79 (rb)^ⁿ
				12.8 (d)^ⁿ
				12.3 (d)^{^p}
		nM
54	MRE-2029-F20	200 (h)^{^ss}	>1000 (h)^{^ss}	5.5 (h)^{^ss}	>1000 (h)^{^ss}
55	PSB-603	>10,000 (h)^{^tt}	>10,000 (h)^{^tt}	0.553 (h)^{^tt}	>10,000 (h)^{^tt}
		>10,000 (r)^{^tt}	>10,000 (r)^{^tt}	K_D 0.403 (h)^{^tt}
				K_D 0.351 (m)^{^tt}
56	CVT-6883	1940 (h)^{^uu}	3280 (h)^{^uu}	22 (h)^{^uu}	1070 (h)^{^uu}
57	PSB-1115	>10,000 (h)^{^u}	24,000 (r)^{^m}	53.4 (h)^{^u}	>10,000 (h)^{^u}
		2200 (r)^{^m}
58	ATL 802	369 (h)^{^rr}	654 (h)^{^rr}	2.36 (h)^{^rr}	>1000 (h)^{^rr}
		9583 (m)^{^rr}	8393 (m)^{^rr}	8.58 (m)^{^rr}	>10,000 (m)^{^rr}
59	LAS38096	2821 (h)^{^vv}	>1000 (h)^{^vv}	17 (h)^{^vv}	1043 (h)^{^vv}
A₃-selective antagonists
60	KF26777	1800 (h)^{^ww}	470 (h)^{^ww}	620 (h)^{^ww}	0.20 (h)^{^ww}
61	PSB-10	1700 (h)^{^xx}	2700 (h)^{^xx}	N.D.	0.441 (h)^{^yy}
		805 (r)^{^yy}	6040 (r)^{^yy}
62	PSB-11	1640 (h)^{^xx}	1280 (h)^{^xx}	2100 (m)^{^yy}	2.34 (h)^{^xx}
		440 (r)^{^xx}	2100 (r)^{^xx}		K_D 4.9 (h)^{^zz}
63	MRE-3008-F20	1200 (h)^{^aa}	141 (h)^{^aa}	2100 (h)^{^aa}	0.82 (h)^{^aa}
64	MRS1523	>10,000 (h)^{^aaa}	3660 (h)^{^aaa}	>10,000 (h)^{^aaa}	18.9 (h)^{^aa}
		15,600 (r)^{^aaa}	2050 (r)^{^aaa}	>10,000 (m)^{^aaa}	113 (r)^{^aaa}
					731 (m)^{^aaa}
65	MRS1191	>10,000 (h)^{^aaa}	>10,000 (h)^{^aaa}	>10,000 (h)^{^aaa}	31.4 (h)^{^aaa}
		40,100 (r)^{^aaa}	>10,000 (r)^{^aaa}		1850 (r)^{^aaa}
66	VUF-5574	≤10,000 (r)^{^bbb}	≤10,000 (r)^{^bbb}	N.D.	4.03 (h)^{^bbb}