TABLE 5.
Competition displacement of [3H]olmesartan binding to various AT1R mutants by olmesartan and its derivatives
ΔKi1refers to the WT response for each ligand, to evaluate the effects of each mutation. ΔKi2 refers to each derivative of olmesartan, to evaluate the effects of modifications on ligand. Results are presented as means ± S.E. and represent three experiments performed in triplicate.
| Mutation | Location | Olmesartan |
R239470 |
R781253 |
R794847 |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ki | ΔKi1 | ΔKi2 | ΔKi | ΔKi1 | ΔKi2 | Ki | ΔKi1 | ΔKi2 | Ki | ΔKi1 | ΔKi2 | ||
| WT | 5.3 ± 0.8 | 1.0 ± 0.2 | 1.0 ± 0.2 | 3.4 ± 0.28 | 1.0 ± 0.1 | 0.6 ± 0.1 | 18.2 ± 1.3 | 1.0 ± 0.1 | 3.4 ± 0.3 | 32.8 ± 2.14 | 1.0 ± 0.1 | 6.2 ± 0.6 | |
| Y87A | 2.63 | 5.9 ± 0.8 | 1.1 ± 0.2 | 1.1 ± 0.2 | 29.2 ± 4.1 | 8.6 ± 1.4 | 4.9 ± 0.8 | 32.7 ± 5.0 | 1.8 ± 0.3 | 5.5 ± 0.9 | 518.0 ± 88.0 | 15.8 ± 2.9 | 87.8 ± 15.9 |
| T88A | 2.64 | 10.2 ± 2.2 | 1.9 ± 0.5 | 1.9 ± 0.5 | 14.7 ± 3.1 | 4.3 ± 1.0 | 1.4 ± 0.3 | 9.7 ± 1.1 | 0.5 ± 0.1 | 1.0 ± 0.1 | 11.4 ± 1.9 | 0.3 ± 0.1 | 1.1 ± 0.2 |
| Y92A | ECL1 | 3.8 ± 0.5 | 0.7 ± 0.1 | 0.7 ± 0.1 | 16.7 ± 3.2 | 4.9 ± 1.0 | 4.3 ± 0.9 | 19.3 ± 1.4 | 1.1 ± 0.1 | 5.1 ± 0.5 | 10.9 ± 1.4 | 0.3 ± 0.1 | 2.9 ± 0.4 |
| V108A | 3.32 | 15.3 ± 2.7 | 2.9 ± 0.7 | 2.9 ± 0.7 | 14.6 ± 2.1 | 4.3 ± 0.7 | 1.0 ± 0.2 | 9.1 ± 1.8 | 0.5 ± 0.1 | 0.6 ± 0.1 | 12.33 ± 1.96 | 0.4 ± 0.1 | 0.8 ± 0.1 |
| L112A | 3.36 | 12.1 ± 2.2 | 2.3 ± 0.5 | 2.3 ± 0.5 | 19.2 ± 4.1 | 5.6 ± 1.3 | 1.6 ± 0.4 | 62.7 ± 5.0 | 3.4 ± 0.4 | 5.2 ± 0.6 | 411.0 ± 89.0 | 12.5 ± 2.8 | 34.0 ± 7.7 |
| P162A | 4.59 | 10.6 ± 1.3 | 2.0 ± 0.4 | 2.0 ± 0.4 | 5.6 ± 1.3 | 1.6 ± 0.4 | 1.6 ± 0.4 | 11.9 ± 3.1 | 0.7 ± 0.2 | 0.7 ± 0.2 | 39.9 ± 3.7 | 1.2 ± 0.1 | 1.2 ± 0.1 |
| A163G | 4.60 | 8.0 ± 1.7 | 1.5 ± 0.4 | 1.5 ± 0.4 | 8.3 ± 1.1 | 2.4 ± 0.4 | 2.4 ± 0.4 | 54.7 ± 4.1 | 3.0 ± 0.3 | 3.0 ± 0.3 | 82 ± 6.1 | 2.5 ± 0.2 | 2.5 ± 0.2 |
| K199A | 5.42 | 14.1 ± 1.5 | 2.7 ± 0.5 | 2.7 ± 0.5 | 12.9 ± 2.1 | 3.8 ± 0.7 | 0.9 ± 0.2 | 46.4 ± 4.8 | 2.5 ± 0.3 | 3.3 ± 0.4 | 94.8 ± 8.1 | 2.9 ± 0.3 | 6.7 ± 0.7 |
| N200A | 5.43 | 6.1 ± 1.0 | 1.2 ± 0.2 | 1.2 ± 0.2 | 5.6 ± 0.7 | 1.6 ± 0.3 | 0.9 ± 0.1 | 16.4 ± 2.1 | 0.9 ± 0.1 | 2.6 ± 0.4 | 28.1 ± 3.1 | 0.9 ± 0.1 | 4.6 ± 0.6 |
| W253A | 6.48 | 10.3 ± 0.7 | 1.9 ± 0.3 | 1.9 ± 0.3 | 4.9 ± 1.0 | 1.4 ± 0.3 | 0.5 ± 0.1 | 73.6 ± 5.1 | 4.0 ± 0.4 | 7.1 ± 0.7 | 146.4 ± 15 | 4.5 ± 0.5 | 14.2 ± 1.7 |
| H256A | 6.51 | 2.1 ± 1.0 | 0.4 ± 0.2 | 0.4 ± 0.2 | 6.7 ± 1.1 | 2.0 ± 0.4 | 3.2 ± 0.6 | 47.6 ± 3.2 | 2.6 ± 0.3 | 22.7 ± 2.2 | 15.7 ± 2.9 | 0.5 ± 0.1 | 7.5 ± 1.5 |
| Q257A | 6.52 | 15.6 ± 2.0 | 2.9 ± 0.6 | 2.9 ± 0.6 | 18.0 ± 2.0 | 5.3 ± 0.8 | 1.2 ± 0.2 | 72.2 ± 5.4 | 4.0 ± 0.4 | 4.6 ± 0.5 | 146.5 ± 15.1 | 4.5 ± 0.5 | 9.4 ± 1.1 |
| T260A | 6.55 | 5.7 ± 0.8 | 1.1 ± 0.2 | 1.1 ± 0.2 | 4.8 ± 0.9 | 1.4 ± 0.3 | 0.8 ± 0.2 | 63.5 ± 6.1 | 3.5 ± 0.4 | 11.1 ± 1.3 | 126.3 ± 22.0 | 3.9 ± 0.7 | 22.2 ± 4.1 |
| P285A | 7.36 | 3.7 ± 0.3 | 0.7 ± 0.1 | 0.7 ± 0.1 | 2.7 ± 2.3 | 0.8 ± 0.7 | 0.7 ± 0.6 | 16.4 ± 2.3 | 0.9 ± 0.1 | 4.4 ± 0.7 | 22.2 ± 3.0 | 0.7 ± 0.1 | 6.0 ± 0.9 |