Table 2.
Hydrophilic A-Ring Substitutionsd
| # | R1 | R2 | X | Y | pEC50 [95% CI] (max) (%)a | p(doubling conc.) (GluN2C/2D)b | cLogP | LLE (GluN2C/2D) | |
|---|---|---|---|---|---|---|---|---|---|
| GluN2C | GluN2D | ||||||||
| CIQc | OMe |  |
O | - | 5.3 (230) | 5.3 (220) | 4.9/4.5 | 5.6 | −0.7/−1.1 |
| 117c | H |  |
- | O | 5.9 (240) | 6.0 (220) | 5.5/5.3 | 5.9 | −0.4/−0.6 |
| 12f | H |  |
- | O | 5.1 [4.9–5.3] (290) | 4.7 [4.5–4.9] (450) | 5.0/5.1 | 4.1 | 0.9/1.0 |
| 12g | H |  |
- | O | <4.5 (330) | <4.5 (160) | <4.5/ID | 4.1 | - |
| 12h | H |  |
- | O | ND (97) | ND (94) | - | 4.0 | - |
| 12l | H |  |
- | O | ND (110) | ND (98) | - | 2.9 | - |
| 12i | H |  |
- | O | ND (85) | ND (85) | - | 5.1 | - |
| 12j | H |  |
- | O | ND (98) | ND (100) | - | 3.1 | - |
| 12k | H |  |
- | O | ND (110) | ND (96) | - | 3.6 | - |
Fitted pEC50 values are shown to have two significant figures when potentiation at 30 μM exceeded 130% of control; values in brackets are the 95% confidence interval for the corresponding fitted pEC50 mean value; and values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) current. For compounds in which a pEC50 value was not determined, maximum potentiation is reported as percent potentiation as a percent of control at 30 μM drug. Data are between 6 and 11 oocytes from 2 frogs for each compound and receptor.
p(doubling conc.) is the negative log of the doubling concentration.
Previously published data for CIQ and 117 were included for comparison. Single methoxy substitution on the C-ring maintains similar or better activity to dimethoxy substitution.59
ND = not determined.