Table 1.
Receptor binding affinity (or % inhibition at 10 μM) of truncated (N)-methanocarba nucleosides, including reference compounds 8and 22.
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|---|---|---|---|---|---|
| Compound | R1 = | R2 = | A1AR Binding Ki, nM (species),a or % at 10 μM | hA2AAR Binding Ki, nM,a or % at 10 μM | A3AR Binding Ki, nM (species),a or % at 10 μM |
| 8b | Ph | Ph-(CH2)2 | 30±8% (h) | 22±5% | 20±6 (h), 480±90 (m) |
| 9 | Ph | 3-F-Ph-(CH2)2 | 2680±420 (h) | 27±6% | 35.9±3.3 (h), 264±32 (m) |
| 10 | Ph | 4-OH-Ph-(CH2)2 | 29±2% (h) | 32±11% | 45.6±24.6 (h), 76.4±3.9 (m) |
| 11 | Ph | 3-F-4-OH-Ph-(CH2)2 | 44±1% (h) | 17±8% | 9.03±1.60 (h), 61.6±4.2 (m) |
| 12 | Ph | 4-H2N-Ph-(CH2)2 | 30±3% (h) | 26±9% | 14.2±1.0 (h), 60.4±7.7 (m) |
| 13 | Ph | 3,4-di-OH-Ph-(CH2)2 | 28±6% (h), 1420±100 (m) | 27±7% | 48.8±22.2 (h), 39.8±5.4 (m) |
| 14 | Ph | 3-OH-4-OCH3-Ph-(CH2)2 | 49±8% (h) | 27±10% | 6.85±3.02 (h), 122±23 (m) |
| 15 | Ph | 3-OCH3-4-OH-Ph-(CH2)2 | 33±5% (h), 590±80 (m) | 39±11% | 10.9±4.4 (h), 17.8±2.3 (m) |
| 16 | Ph | 3,4-di-OCH3-Ph-(CH2)2 | 208±25 (h) | 28±13% | 16.3±2.8 (h), 331±54 (m) |
| 17 | 2-F-Ph | 3-OCH3-4-OH-Ph-(CH2)2 | 186±31 (h), 620±78 (m) | 5850±841 | 5.42±1.06 (h), 21.5±1.9 (m) |
| 18 | 3-F-Ph | 3-OCH3-4-OH-Ph-(CH2)2 | 38±9% (h) | 51±2% | 4.63±1.20 (h), 72.2±4.4 (m) |
| 19 | 4-F-Ph | 3-OCH3-4-OH-Ph-(CH2)2 | 39±5% (h) | 51±2% | 6.51±1.74 (h), 54.4±3.3 (m) |
| 20 | 3,4-F2-Ph | 3-OCH3-4-OH-Ph-(CH2)2 | 341±36 (h) | 33±3% | 12.8±1.1 (h), 75.0±7.4 (m) |
| 21 | 3-pyridyl | 3-OCH3-4-OH-Ph-(CH2)2 | 36±5% (h) | 39±3% | 6.70±2.12 (h), 155±10 (m) |
| 22b | 2-Cl-Ph | Ph-(CH2)2 | 37±7% (h) | 26±10% | 37.0±7.0 (h), 980±74 (m) |
| 23 | 5-Cl-thienyl | Ph-(CH2)2 | 10±3% (h) | 46±9% | 8.17±1.94 (h), 995±19 (m) |
| 24 | 5-Cl-thienyl | 3-F-Ph-(CH2)2 | 31±3% (h) | 55±3% | 42.2±12.4 (h), 488±20 (m) |
| 25 | 5-F-thienyl | 3-F-Ph-(CH2)2 | 2290±90 (h) | 48±40% | 55.8±15.7 (h), 404±55 (m) |
| 26 | 5-Cl-thienyl | 3-Cl-Ph-(CH2)2 | 39±3% (h) | 59±4% | 58.4±3.1 (h), 531±10 (m) |
| 27 | 5-Cl-thienyl | 3-CH3-Ph-(CH2)2 | 29±4% (h) | 50±0% | 106±10 (h), 675±34 (m) |
| 28 | 5-Cl-thienyl | 3,4-F2-Ph-(CH2)2 | 28±10% (h) | 57±1% | 47.1±10.6 (h), 2520±260 (m) |
| 29 | 5-Cl-thienyl | 3-OCH3-4-OH-Ph-(CH2)2 | 649±146 (h) | 38±0% | 9.52±0.50 (h), 74.7±9.8 (m) |
| 30 | 5-Br-thienyl | 3-OCH3-4-OH-Ph-(CH2)2 | 15±3% (h), 2840±170 (m) | 38±2% | 3.24±0.14 (h), 26.0±1.7 (m) |
| 31 | 5-Cl-thienyl | Ph-cPr (1S,2R) | 32±6% (h) | 44±0% | 80.5±1.8 (h), 1140±70 (m) |
| 32 | - | 3-OCH3-4-OH-Ph-(CH2)2 | 50±11% (h) | 49±3% | 9.1±1.5 (h), 92.5±18.3 (m) |
Binding in membranes of HEK293 cells stably expressing mA1, mA3, hA1, hA2A or hA3, unless noted.28 The binding affinity for hA1, hA2A and A3ARs was expressed as Ki values using agonists [3H]N6-R-phenylisopropyladenosine ([3H]R-PIA, 0.5 nM) 33, [3H]2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine ([3H]CGS21680, 5 nM) 34, or [125I]N6-(4-amino-3-iodobenzyl)-adenosine-5′-N-methyluronamide ([125I]I-AB-MECA, 0.1 nM) 35, respectively. A percent in italics refers to inhibition of specific radioligand binding at 10 μM. Nonspecific binding was determined using N-(2-aminoethyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]-acetamide (XAC) 36 (10 μM). The binding affinity at mARs was determined as reported.23 Values are expressed as the mean ± SEM (n = 3, unless noted). Ki values were calculated as reported.31 The HEK293 cell lines were from American Type Culture Collection (ATCC, Manassas, VA), and the cDNA for the ARs was obtained from cdna.org.
ND, not determined.