Table 3.
Binding affinity of a series of adenosine C2 long chain amide derivatives of 16 at three subtypes of human ARs.
 | |||||
|---|---|---|---|---|---|
| Compd | R = | Affinity Ki, nM or (% inhibition)a |
Efficacy (A2A), % of maximalb |
||
| A1 | A2A | A3 | |||
| 16 | OH | 380 | 70 | 570 | 100 |
| 27 | L-Phe-OMe | 1080 ± 210 | 160 ± 50 | 130 ± 40 | 110.9 ± 2.5 |
| 28 | D-Phe-OMe | 1230 ± 180 | 84.3 ± 3.0 | 160 ± 80 | 92.6 ± 12.4 |
| 29 | L-Trp-OMe | 1670 ± 260 | 87.2 ± 3.8 | 140 ± 10 | 104.5 ± 13.6 |
| 30 | D-Trp-OMe | 1610 ± 100 | 130 ± 4 | 250 ± 90 | 118.6 ± 5.7 |
| 33 | L-Asp-OH | 1900 ± 660 | 180 ± 60 | 1460 ± 600 | 94.8 ± 6.7 |
| 34 | D-Asp-OH | 1180 ± 360 | 110 ± 10 | 790 ± 160 | 94.3 ± 7.3 |
| 35 | L-Arg-OH | 1110 ± 30 | 100 ± 4 | 620 ± 250 | 94.5 ± 5.8 |
| 36 | D-Arg-OH | 990 ± 320 | 50 ± 5 | 220 ± 60 | 94.7 ± 6.7 |
| 37 | L-Phe-OH | 640 ± 170 | 63.7 ± 13.1 | 260 ± 140 | 103.3 ± 13.8 |
| 38 | D-Phe-OH | 550 ± 100 | 34.0 ± 3.2 | 140 ± 30 | 93.4 ± 12.4 |
| 39 | L-Trp-OH | 1060 ± 310 | 71.7 ± 16.9 | 200 ± 50 | 95.8 ± 7.4 |
| 40 | D-Trp-OH | 2160 ± 280 | 130 ± 30 | 520 ± 60 | 113.3 ± 5.0 |
| 41 | L-His-OH | 1000 ± 160 | 110 ± 30 | 830 ± 290 | 105.2 ± 4.9 |
| 42 | D-His-OH | 350 ± 40 | 40 ± 4 | 320 ± 150 | 105.9 ± 6.5 |
a
Using CHO or HEK293 (A2A only) cells stably expressing a human AR (Supporting Information); affinity was expressed as Ki value (n = 3–5) or percent inhibition of radioligand binding at 10 µM. Compounds 31 and 32 are conjugates of L- and D-His-OMe, respectively, and were not tested biologically.
b
Maximal efficacy (at 10 µM) in an A2AAR functional assay, determined by stimulation of cyclic AMP production in stably transfected CHO cells, expressed as percent (mean ± standard error, n = 3 – 5) in comparison to effect (100%) of full agonist 16 at 10 µM.