Table 1. Radioligand Uptake and Binding Data at DAT and SERTa.
| uptake
inhibition |
binding inhibition |
ratio |
pharmacochaperoning |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| IC50 ± SD (μM) |
Ki ± SD (μM) |
IC50/Ki |
EC50 ± SD (μM) | Vmax (%) | EC50 ± SD (μM) | Vmax (%) | ||||
| WT-SERT | WT-DAT | WT-SERT | WT-DAT | WT-SERT | WT-DAT | SERT-PG601,602AA | DAT-PG584,585AA | |||
| ibogaine | 8.2 ± 3.5 | 22.1 ± 6.3 | 7.4 ± 0.7 | 5.3 ± 1.7 | 1.1 | 4.2 | 2.6 ± 1.9 | 103 ± 16 | 19.6 ± 4.9 | 88 ± 16 |
| noribogaine | 1.2 ± 0.5 | 15.5 ± 7.8 | 0.6 ± 0.1 | 4.0 ± 1.8 | 2.1 | 3.9 | 4.6 ± 1.2 | 100 ± 8 | 17.1 ± 6.1 | 100 ± 13 |
| 3a | 9.1 ± 3.1 | 25.6 ± 10.2 | 1.2 ± 0.2 | 3.1 ± 0.9 | 7.8 | 8.2 | NC* | 19 ± 6* | NC* | 15 ± 10* |
| 3b | 6.5 ± 5.2 | 24.4 ± 17.9 | 1.85 ± 0.3 | 1.7 ± 0.1 | 3.5 | 14.4 | 12.9 ± 6.3 | 60 ± 17 | NC* | 15 ± 8* |
| 3c | 0.5 ± 0.1 | 9.09 ± 1.64 | 0.19 ± 0.03 | 4.4 ± 1.4 | 2.4 | 2.1 | 2.7 ± 0.78 | 57 ± 13 | 17.1 ± 5.6 | 47 ± 18 |
| 3d | 11.9 ± 1.6 | 58.2 ± 41.4 | 4.5 ± 0.4 | 8.8 ± 4.9 | 2.6 | 6.6 | NC* | 11 ± 3* | NC* | 20 ± 15* |
| 3e | 21.6 ± 17.4 | 179 ± 94 | 13.0 ± 2.7 | 10.2 ± 3.8 | 1.7 | 17.6 | NC* | 38 ± 19* | NC* | 15 ± 9* |
| 3f | 0.2 ± 0.1 | 78.0 ± 27.9 | 0.12 ± 0.02 | 21.8 ± 9.4 | 1.6 | 3.6 | NC* | 8 ± 2* | NC* | 13 ± 10* |
| 4a | 4.6 ± 2.63 | 6.5 ± 2.1 | 0.81 ± 0.03 | 1.9 ± 0.2 | 5.7 | 3.5 | NC* | 25 ± 6* | NC* | 15 ± 9* |
| 4b | 8.2 ± 1.0 | 11.9 ± 1.6 | 1.7 ± 0.3 | 1.5 ± 0.3 | 4.8 | 7.7 | NC* | 29 ± 8* | NC* | 10 ± 6* |
| 4c | 0.3 ± 0.2 | 11.8 ± 9.1 | 0.13 ± 0.34 | 2.6 ± 0.7 | 2.5 | 4.5 | 0.7 ± 0.3 | 68 ± 16 | NC* | 24 ± 8* |
| 8a | ND | ND | >100 | 39.7 ± 27.9 | ND | ND | ND | ND | ND | ND |
| 8b | ND | ND | >100 | 51.2 ± 14.6 | ND | ND | ND | ND | ND | ND |
| 8c | ND | ND | >100 | 45.78 ± 6.5 | ND | ND | ND | ND | ND | ND |
| 9a | 6.9 ± 3.9 | 16.7 ± 11.2 | 4.4 ± 0.2 | 3.6 ± 0.2 | 1.6 | 4.6 | 3.05 ± 2.3 | 94 ± 23 | 18.9 ± 2.9 | 51 ± 21 |
| 9b | 0.4 ± 0.2 | 7.2 ± 3.8 | 0.18 ± 0.01 | 0.8 ± 0.3 | 2.3 | 8.9 | 0.06 ± 0.04 | 100 ± 6 | 25.7 ± 6.3 | 673 ± 245 |
| 9c | 29.9 ± 16.4 | 10.8 ± 9.3 | 7.3 ± 0.5 | 3.1 ± 0.3 | 4.1 | 3.5 | 2.1 ± 0.8 | 81 ± 20 | 19.2 ± 8.7 | 53 ± 13 |
| 9d | 0.9 ± 0.5 | 15.2 ± 9.7 | 0.78 ± 0.04 | 2.9 ± 0.3 | 1.2 | 5.3 | 1.4 ± 0.8 | 89 ± 19 | 5.8 ± 1.9 | 49 ± 30 |
a
Each IC50, Ki, Km and Vmax value represents data from at least 3 independent experiments, each performed in triplicate. Vmax refers to the maximum transport restored by noribogaine, which was set at 100% to account for interassay variation. Experimental procedures are described in detail in the “Materials and Methods” section. NC*: not calculable, a reliable EC50 could not be estimated, because functional rescue was too low; in this instance Vmax* refers to the activity restored by 30 μM of the compound. ND: not determined.