Table 1.

Structures and binding affinities^a of AR ligands in the species indicated, including reference compounds 1 - 7 and 15 - 18. R³ = OH, R⁴ = NHCH₃, Y = N, unless noted.

Compd. (other changes)	R1	R2	A1AR % inhibition or Ki (nM)a	A2AAR % inhibitiona	A3AR % inhibition or Ki (nM)a	Off-target, receptor (h, unless noted) (Ki, μM)a
Ribosides, 5′-OH or 5′-Cl
1ac,d		H	2.3 (h), 0.22±0.01 (m)	794 (h), 808±89 (m)	72±12 (h), 534±14 (m)	ND
2c,d		Cl	0.83 (h), 0.21±0.10 (m)	2270 (h), 988 (m)	38±6 (h), 17±5 (m)	ND
5f (R3 = S-(2-F)-Ph)		H	12 (h)	>10,000 (h)	>1000 (h)	ND
8b		H	0.85±0.27 (h), 0.8 (r)	1470±380 (h), 1370 (r)	41.3±5.3 (h)	none
9		H	2.14±0.52 (h), 0.37±0.02 (m)	3550±440 (h)	10,600±1400 (h), 897±45 (m)	DAT 1.78, NET 4.82
10 (R3 = Cl)		H	4.90±0.87 (h), 0.71±0.12 (m)	5200i (h)	16,600±2000 (h), 2110±50 (m)	TSPO 3.98, σ1 0.69, σ2 0.662
11 (R3 = SCH2CH3)		H	63.4±12.1 (h), 3.58±0.01 (m)	30±5% (h)	6220±1480 (h), 718±150 (m)	TSPO (90% inhib.j) σ1 0.626, σ2 0.642
12		Cl	17.8±8.7 (h), 0.65±0.06 (m)	2550±540 (h)	13,200±2500 (h), 653±85 (m)	5HT2C 1.45
3c,d		H	0.38±0.19 (h), 0.34 (r), 0.14±0.02 (m)	>10,000 (h), 477 (r)	915±299 (h), 282 (r), 424±41 (m)	ND
4c (R3 = Cl)	(±)	H	0.51 (h), 0.20±0.01 (m)	1340 (h), 3990±360 (m)	1290 (h), 2410±330 (m)	ND
13c (R3 = Cl)		H	0.76±0.42 (h)	2050±570 (h)	355±117 (h), 1560±140 (m)	σ1 0.484, σ2 0.432, 5HT7 1.24
Ribosides, 4′-carbonyl derivatives
14 (R4 = OH)	H	H	24±4% (h)	11±4% (h)	32±9% (h)	BZP (r) 7.34, σ1 1.48, σ2 0.796
15d (R3 = NH-Me)	H	H	36.7±9.4 (h), 84 (r)	466±95 (h), 67 (r)	24.4±7.9 (h), 63 (r)	none
16c,d,h (R4 = NH-Et)	H	H	6.8±2.4 (h),g 3.00±0.10 (h), 0.45±0.13 (m), 63 (r)	2.2±0.6 (h),g 35.0±14.0 (h), 12 (r)	35±12 (h), 14.1±6.8 (m), 113 (r)	none
17d (R4 = NH-cPr)	H	H	1.90±0.60 (h), 6.4 (r)	50±10 (h), 13.4 (r)	180±50 (h), 1600 (r)	H1 7.88, σ1 4.12 (gp), σ2 4.35
18d,h (R4 = NH-(CH2)2OH)	H	H	12.8±3.1 (h)	505±30 (h)	9450±1760 (h)	ND
(N)-Methanocarba, 4′-truncated
7c		Cl	47.9±10.5 (h), 5.20±0.05 (m)	3950±410 (h), 34±9% (m)	470±15 (h), 1060±250 (m)	5HT2B 0.641, 5HT2C 1.85
19		Cl	961±639 (h)	46±6% (h)	822±449 (h), 385±52 (m)	5HT2B 2.90, 5HT2C 8.32, α2A 6.96, TSPO 2.38
20b		Cl	34±3% (h)	13±3% (h)	48±2% (h)	5HT2C 2.92, σ1 5.09, σ2 2.01
(N)-Methanocarba, 5′-OH or 5′-Cl
21b	H	Cl	105±63 (h), 273 (r)b	3420±270 (h), 1910 (r)b	353±54 (h)d	none
22 (R3= Cl)	H	Cl	7.61±0.73 (h)	1750±290 (h)	253±148 (h)	σ1 1.97, σ2 2.55
23b		Cl	39±17 (h), 0.71±0.06 (m)	2200 (h), 41±9% (m)	1600±210 (h), 1030±40 (m)	5HT2B 0.641, 5HT2C 1.85, DAT 4.75
24		H	22.7±3.0 (h), 0.53±0.19 (m)	34±1% (h)	51±6% (h), 918±21 (m)	BZP (r) 4.08, 5HT2B 0.214, 5HT2C 1.32, σ1 1.79, σ2 0.753
25		Cl	8.96±1.02 (h), 2.47±0.26 (m)	55±5% (h), 26±3% (m)	25±2% (h), 612±58 (m)	5HT2B 0.153, 5HT2C 0.238, M5 3.00, DAT 4.75 TSPO 2.93
26 (R3 = Cl)		H	32.7±12.4 (h), 1.05±0.19 (m)	38±3% (h)	49±4% (h), 934±18 (m)	5HT2B 2.01, α2A 6.80, σ1 1.50, σ2 1.17, TSPO, 2.02
27 (R3 = Cl)		Cl	120±23 (h), 11.2±0.8 (m)	17±24% (h), 20±3% (m)	3820±1820 (h), 1560±60 (m)	5HT2B 1.52, 5HT2C 1.75, H2 2.60, σ2 0.349, TSPO, 2.89
28 (R3 = S-(2-F)-Ph)		Cl	45±4% (h), 2490±280 (m)	22±5% (h), 20±9% (m)	9750±4030 (h), 7440±660 (m)	5HT2B 0.334, 5HT2C 1.46, σ2 0.583
29		Cl	23.6±5.2 (h), 1.05±0.03 (m)	4260i (h), 15±2% (m)	288±54 (h), 574±23 (m)	5HT2B 0.472, NET 5.74
30 (Y = CH)		Cl	240±19 (h)	29±3% (h)	145±74 (h)	none
31 (R3 = Cl)		Cl	44.8±1.3 (h), 1.86±0.10 (m)	54±8% (h), 15±1% (m)	456±201 (h), 503±13 (m)	none
(N)-Methanocarba, 5′-carbonyl
32b (R4 = O-Et)		Cl	360±74 (h)	1570±180 (h)	236±41 (h)	5HT2B 0.015, 5HT2C 0.054, TSPO 2.50
33 (R4 = O-Et, 2′,3′-C(CH3)2)		Cl	49±9% (h)	15±2% (h)	41±6% (h)	5HT5A 8.69, H2 6.38
34b (R4 = NH-Me)		Cl	110±14 (h)	4320±870 (h)	34±11 (h)	5HT2B 0.023, 5HT2C 0.749
35 (R4 = O-Et)		Cl	73.8±14.2 (h)	57±12% (h)	1160±300 (h)	5HT2B 0.097, 5HT2C 0.089, M3 5.90, σ2 2.02
6e (R4 = NH-Me)		Cl	18.3±6.3 (h), 0.68±0.02 (m)	3250±300 (h)	3.7±0.9 (h), 5.8±1.6 (r), 3.46±0.13 (m)	5HT2B 0.012, σ1 1.55
36 (R4 = NH-cPr)		Cl	1.22±0.05 (h), 0.45±0.03 (m)	520±119 (h), 2650±560 (m)	59.0±17.8 (h), 29.5±0.6 (m)	5HT2B 1.57
37 (R4 = NH-(CH2)2OH)		Cl	17.6±5.3 (h), 1.56±0.09 (m)	5400i (h), 23±1% (m)	127±29 (h), 447±43 (m)	5HT2B 0.718, KOR, 2.63
Ribavirin analogues
38g	-	-	7410±100 (h), 4430±460 (m)	23±6% (h)	16±5% (h), 0% (m)	ND
39	OCH3	-	6±4% (h), 2990±80 (m)	14±5% (h)	22±4% (h), 15±2% (m)	β3 1.42, H3 4.52, σ2 1.72
40	NH2	-	495±35 (h), 25.2±2.8 (m)	11±3% (h)	41±6% (h), 47±2% (m)	5HT2B 1.91, 5HT2C 2.35, DAT 6.61, σ2 2.09

^aBinding in membranes of CHO or HEK293 (A_2A only) cells stably expressing one of three hAR subtypes, unless noted (n = 3–5). The binding affinity for hA₁, A_2A and A₃ARs was expressed as K_i values using agonists [³H]N⁶-R-phenylisopropyladenosine 51, [³H]2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine 52, or [¹²⁵I]N⁶-(4-amino-3-iodobenzyl)adenosine-5′-N-methyluronamide 53, respectively. A percent in italics refers to inhibition of binding at 10 μM. Nonspecific binding was determined using adenosine 5′-N-ethyluronamide 54 (10 μM). Values are expressed as the mean ± SEM (n = 3, unless noted). K_i values were calculated as reported.⁴² Off-target interactions determined by the PDSP. Receptor abbreviations are defined in the Supporting Information. Gp, guinea pig.

^bData from Tosh et al.^33,34

^cData from Carlin et al.³⁰ and van der Hoeven et al.⁴³

^dData from Gao et al.,¹⁷ Tosh et al.²³ and Gallo-Rodriguez et al., 1994.⁴⁵

^eData from Jacobson et al.³²

^fData from Kiesman et al., 2009; Müller and Jacobson, 2011.^1,35

^gData from Jacobson et al.⁴⁴ and Rodríguez et al.³⁶

^hFunctional EC₅₀ (nM) at hA_2BAR: 16, 140±19; 18, 948±38.⁴⁴

ⁱn = 1.

^jPercent inhibition at 10 μM.

ND, not determined.