Table 2. Binding Affinities and Kinetic Parameters of Pyrido[2,1-f]purine-2,4-dione Derivatives with Modification on N-3 Position (R1 Group).
| compd | R1 | pKia ± SEM (mean Ki in nM) | KRIb | konc (M–1 s–1) | koffd (s–1) | RTe (min) |
|---|---|---|---|---|---|---|
| 5 | H | 7.0 ± 0.02 (108) | 0.38 ± 0.12 | (5.3 ± 1.5) × 105 | (1.4 ± 0.5) × 10–2 | 2.2 ± 1.4 |
| 6 | CH3 | 7.7 ± 0.1 (20.8) | 0.54 (0.52, 0.55) | ndf | nd | nd |
| 7 | CH2CH3 | 8.0 ± 0.1 (10.7) | 0.80 (0.85, 0.75) | nd | nd | nd |
| 8 | CH2CH2CH2CH3 | 8.8 ± 0.1 (1.5) | 1.29 (1.27, 1.31) | nd | nd | nd |
| 9 | CH2CH2CH2CH2CH3 | 8.5 ± 0.02 (3.5) | 1.11 (0.98, 1.24) | (1.1 ± 0.1) × 106 | (6.0 ± 0.5) × 10–4 | 28 ± 2.2 |
| 10 | CH2CH2CH2CH2CH2CH3 | 8.6 ± 0.1 (2.8) | 2.18 (2.15, 2.21) | (2.3 ± 1.0) × 105 | (8.2 ± 1.3) × 10–5 | 213 ± 35 |
| 11 | CH2CH2CH2CH2CH2CH2CH3 | 8.2 ± 0.2 (6.8) | 4.06 (3.66, 4.46) | (4.2 ± 0.3) × 105 | (6.2 ± 0.2) × 10–5 | 278 ± 45 |
| 12 | CH2CH=CH2 | 8.3 ± 0.1 (5.9) | 0.72 (0.46, 0.99) | nd | nd | nd |
| 13 | CH2C≡CH | 8.4 ± 0.02 (4.3) | 1.20 (1.16, 1.23) | nd | nd | nd |
| 14 | CH2CH2CH=CH2 | 8.9 ± 0.1 (1.4) | 1.23 (1.04, 1.41) | nd | nd | nd |
| 15 | CH2CH2OCH3 | 7.7 ± 0.2 (23) | 0.70 (0.70, 0.70) | (4.3 ± 0.8) × 105 | (6.3 ± 0.7) × 10–4 | 27 ± 2.6 |
| 16 | CH2CH2CH2OH | 7.1 ± 0.1 (81) | 1.04 ± 0.11 | nd | nd | nd |
| 17 | CH2CH(CH3)2 | 8.9 ± 0.02 (1.2) | 1.64 ± 0.24 | (7.8 ± 2.7) × 105 | (2.0 ± 0.8) × 10–4 | 148 ± 102 |
| 18 | CH2C(CH3)3 | 8.5 ± 0.1 (3.5) | 1.73 ± 0.28 | (5.5 ± 1.3) × 105 | (1.1 ± 0.4) × 10–4 | 250 ± 147 |
| 19 | CH2CH2CH(CH3)2 | 8.5 ± 0.04 (3.5) | 1.39 (1.23; 1.55) | nd | nd | nd |
| 20 | CH2CH2C(CH3)3 | 8.1 ± 0.02 (8.0) | 0.95 (1.02, 0.87) | nd | nd | nd |
| 21 | CH2Si(CH3)3 | 8.6 ± 0.03 (2.7) | 1.36 (1.26, 1.45) | nd | nd | nd |
| 2 | CH2C3H5 | 9.0 ± 0.02 (1.0) | 2.68 ± 0.48 | (2.8 ± 0.5) × 106 | (6.0 ± 1.7) × 10–5 | 315 ± 105 |
| 22 | CH2C4H7 | 8.6 ± 0.03 (2.7) | 1.48 (1.66, 1.30) | nd | nd | nd |
pKi ± SEM (n ≥ 3, average Ki value in nM), obtained at 25 °C from radioligand binding assays with [3H]34 on human adenosine A3 receptors stably expressed on CHO cell membranes.
KRI ± SEM (n = 3) or KRI (n = 2, individual estimates in parentheses), obtained at 10 °C from dual-point competition association assays with [3H]34 on human adenosine A3 receptors stably expressed on CHO cell membranes.
kon ± SEM (n ≥ 3), obtained at 10 °C from competition association assays with [3H]34 on human adenosine A3 receptors stably expressed on CHO cell membranes.
koff ± SEM (n ≥ 3), obtained at 10 °C from competition association assays with [3H]34 on human adenosine A3 receptors stably expressed on CHO cell membranes.
RT (min) = 1/(60 × koff).
nd = not determined.