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. 2017 Aug 14;60(17):7555–7568. doi: 10.1021/acs.jmedchem.7b00950

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).

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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
a

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.

b

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.

c

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.

d

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.

e

RT (min) = 1/(60 × koff).

f

nd = not determined.