TABLE 4.
Ki values and selectivity ratios for the inhibition of purified Na,K-ATPase isoforms by perhydro-1,4-oxazepine derivatives of digoxin
The reaction medium contained 130 mm NaCl, 5 mm KCl, 3 mm MgCl2, 25 mm histidine, pH 7.4, 1 mm EGTA, 0.01 mg/ml SOPS, 0.001 mg/ml cholesterol, and 0.005 mg/ml C12E8. Each experiment was carried out at least three times. The calculated Ki values represent averages ± S.E. *, compounds with significantly higher selectivity (Ki α1β1/α2β1–3) than digoxin (>4- and <10-fold). **, compounds with the highest selectivity (Ki α1β1/α2β1–3) compared with digoxin (>12-fold).
| CG |
Ki ± S.E. |
Selectivity |
n | |||||
|---|---|---|---|---|---|---|---|---|
| α1β1 | α2β1 | α2β2 | α2β3 | α1β1/α2β1 | α1β1/α2β2 | α1β1/α2β3 | ||
| nm | ||||||||
| Digoxin | 268.0 ± 13.8 | 58.7 ± 5.4 | 58.0 ± 1.9 | 42.8 ± 3.0 | 4.5 | 4.6 | 6.2 | 7 |
| DMe | 103.0 ± 5.6 | 15.3 ± 1.2 | 20.4 ± 1.8 | 10.8 ± 0.6 | 6.7* | 5.1 | 9.5* | 7 |
| DEt | 137.9 ± 12.6 | 23.2 ± 0.9 | 16.4 ± 1.6 | 14.4 ± 1.3 | 5.9 | 8.3* | 9.5* | 4 |
| DP | 87.7 ± 7.9 | 18.3 ± 1.7 | 10.5 ± 1.8 | 9.8 ± 1.1 | 4.8 | 8.3* | 8.8* | 5 |
| DiP | 149.0 ± 20.7 | 28.9 ± 1.7 | 16.7 ± 1.9 | 10.3 ± 1.8 | 5.1 | 8.9* | 14.4** | 4 |
| DcP | 109.0 ± 6.2 | 14.6 ± 11.6 | 13.0 ± 1.3 | 8.1 ± 1.36 | 7.5* | 8.5* | 13.4** | 3 |
| DiB | 92.0 ± 8.9 | 20.6 ± 1.4 | 10.0 ± 0.8 | 5.8 ± 0.6 | 4.4 | 9.0* | 16.0** | 5 |
| DMcP | 95.8 ± 13.7 | 18.3 ± 1.6 | 8.0 ± 0.8 | 4.3 ± 0.6 | 5.2 | 12.0** | 22.2** | 4 |
| DcB | 135.0 ± 11.0 | 8.0 ± 1.3 | 6.0 ± 1.0 | 4.0 ± 0.15 | 16.9** | 22.2** | 33.6** | 3 |
| DAz | 222.0 ± 11.6 | 52.0 ± 1.7 | 28.0 ± 3.8 | 26.5 ± 2.3 | 4.2 | 7.7* | 8.4* | 3 |
| DTh | 260.0 ± 41.0 | 108.0 ± 22.6 | 170.0 ± 10.4 | 196.0 ± 34.8 | 2.4 | 1.5 | 1.3 | 3 |
| DcPe | 138.0 ± 21.0 | 33.4 ± 7.5 | 33.5 ± 11.9 | 27.6 ± 9.5 | 4.1 | 4.1 | 5.0 | 3 |
| DcHe | 70.4 ± 4.1 | 15.2 ± 3.7 | 15.3 ± 2.9 | 11.7±.5 | 4.6 | 4.6 | 10.1* | 3 |
| DcB2,2dM | 102.0 ± 4.0 | 49.0 ± 18.0 | 39.0 ± 6.0 | 45.0 ± 14.0 | 2.1 | 2.6 | 2.3 | 3 |
| DMcB3,3dM | 31.6 ± 0.5 | 8.6 ± 1.4 | 5.1 ± 0.5 | 3.9 ± 0.7 | 3.7 | 6.2 | 8.2* | 5 |
| DMSM | 944.0 ± 123.0 | 137.0 ± 9.8 | 123.0 ± 7.3 | 89.0 ± 8.7 | 6.9* | 7.7* | 10.6* | 3 |
| DEMS | 464.0 ± 14.0 | 49.2 ± 1.9 | 31.7 ± 3.2 | 24.7 ± 2.1 | 9.4* | 14.6** | 18.8** | 3 |
| DESA | 301.0 ± 23.0 | 38.9 ± 2.2 | 31.5 ± 4.4 | 20.1 ± 0.9 | 7.7* | 9.5* | 15** | 4 |