Table 1.
Binding affinities and maximal agonist effects of adenosine derivatives (upon structural variation at N6 and C2 positions) at human A1, A2A, A2B, and A3ARs and at rat A3ARs expressed in CHO (Chinese hamster ovary) cellsa
| # | N6-R1 | C-2 |
Ki (hA1AR)a or % displ. |
% Act. (hA1AR)b |
Ki (hA2AAR)a or % displ. |
% Act. (hA2AAR)b |
% Act. (hA2BAR)b |
Ki (hA3AR)a |
% Act. (hA3AR)b |
Ki (rA3AR)a |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | CH3 | H | 5970±2030 | 38±10 | 17% | 5±5 | 16±3 | 9.3±0.4 | 96±3 | 6390 |
| 2 | CH3 | CN | 69.8±4.4 | 60±7 | 23% | 0 | 0 | 3.4±0.8 | 101±7 | >10,000 |
| 3 | CH3 | CF3 | 4650±580 | 4±3 | 9% | 20±3 | 0 | 64.5±3.8 | 93±3 | >10,000 |
| 4 | CH3 | NH2 | 484±22 | 13±2 | 15% | 29±6 | 11±2 | 39.0±2.4 | 98±3 | >10,000 |
| 5 | CH3 | CH2NH2 | 27% | 32±4 | 25% | 30±3 | 4±2 | 719±37 | 57±4 | >10,000 |
| 6 | CH3 | CH(=NH)– NHCH3 |
10% | 8±5 | 9% | 12±3 | 13±8 | 2730±268 | 7±1 | ND |
| 7 | IB | H | 7.4±1.7 | 78±6 | 135±22 | 90±7 | 58±1 | 5.8±0.4 | 46±8 | 9.5±1.4c |
| 8 | IB | Cl | 16.8±2.2 | 8±3 | 197±34 | 99±2 | 16±3 | 1.8±0.1 | 0 | 2.7±1.2 |
| 9 | IB | I | 191±12 | 0 | 1910±320 | 92±8 | 9±6 | 24.3±3.1 | 0 | ND |
| 10 | IB | CN | 1750±290 | 1±1 | 25% | 32±5 | 0 | 119±19 | 0 | 256±30 |
| 11 | IB | CF3 | 612±131 | 0 | 35% | 61±3 | 15±2 | 138±7 | 0 | 257±19 |
| 12 | IB | CO2CH3 | 73.1±22.9 | 38±4 | 390±160 | 91±9 | 18±2 | 3.21±0.17 | 0 | 6.05±0.16 |
| 13 | IB | CONH(3-IB) | 500±160 | 66±16 | 3990±150 | 52±18 | 5±2 | 133±19 | 0 | ND |
| 14 | CMB | H | 9.2±0.5 | 98±8 | 399±6 | 93±6 | 56±4 | 1.31±0.16 | 53±3 | ND |
| 15 | CMB | CN | 63.2±16.9 | 36±13 | 1260±190 | 90±15 | 16±3 | 2.76±0.51 | 29±6 | 12.8±2.3 |
| 16 | CMB | COOH | 41% | 33±10 | 9% | 31±6 | 6±7 | 211±36 | 0 | 698±100 |
| 17 | CMB | CO2CH3 | 6200±790 | 30±4 | 35% | 74±3 | 6±4 | 8.04±0.4 | 35±4 | ND |
| 18 | PC | H | 124±30 | 101±13 | 2530±720 | 88±23 | 20±15 | 0.86±0.09 | 101±5 | 399±28 |
| 19 | PC | CN | 1750±280 | 28±14 | 5640±780 | 51±8 | 6±4 | 8.7±2.1 | 0 | ND |
| 20 | PC | COOH | 30% | 6±2 | 0% | 5±5 | 3±1 | 1730±540 | 28±1 | ND |
| 21 | PC | CONH2 | 295±25 | 98±7 | 41% | 94±4 | 16±3 | 19.7±0.4 | 74±6 | ND |
a
All AR binding experiments were performed using adherent CHO cells stably transfected with cDNA encoding the human or rat ARs (unit: nM). Radioligands: 2nM [3H]R-PIA (A1), 15nM [3H]CGS21680 (A2A), and 0.5nM [125I]I-AB-MECA (A3). % displacement at 10 μM.
b
Percent activity at 10 μM, relative to 10 μM CPA (A1), 10 μM NECA (A2A, A2B), or 10 μM Cl-IB-MECA (A3). Values are expressed as mean±sem, n = 3–5.
c
Data from Kim et al.25 ND, not determined. IB, 3-iodobenzyl; CMB, 5-chloro-2-methyloxybenzyl; PC, trans-2-phenyl-1-cyclopropyl.