TABLE 3.
Correlation between neurosteroid modulation of tonic current and anticonvulsant profiles in the 6-Hz seizure model in mice
E1 μM values represent the mean normalized tonic current responses of drug at 1 μM concentration coapplied with 1 μM GABA. The GABA 1 μM tonic current was 0.66 ± 0.22 pA/pF, 19.6 pA. E3μMvalues represent the mean normalized tonic current responses of drug at 3 μM concentration coapplied with 1 μM GABA. The GABA 3 μM tonic current was 1.35 ± 0.23 pA/pF, 33.5 pA. EF values represent the effective functional concentration of drug (nanomolar) required to double or triple the 1 μM GABA response. The 6-Hz test ED50 values represent the dose in milligrams per kilogram that protected 50% of animals in the 6-Hz seizure stimulation test. 95% confidence intervals are listed in parentheses, according to a normal distribution.
| Compound | E1 μM | E1 μM | E3 μM | E3 μM | EF(2-Fold GABA) | EF(3-Fold GABA) | 6-Hz Test ED50 |
|---|---|---|---|---|---|---|---|
| pA/pF | pA | pA/pF | pA | nM | nM | mg/kg | |
| 3α5αAP | 2.88 ± 0.50 | 100.6 | 7.25 ± 0.40 | 223.7 | 80 | 290 | 4.2 (2.7–5.8) |
| GX | 2.29 ± 0.41 | 64.0 | 5.87 ± 0.50 | 176.1 | 290 | 650 | 1.5 (1.3–1.7) |
| 3α5β-AP | 1.48 ± 0.13 | 44.4 | 4.27 ± 0.25 | 181.7 | 780 | 1380 | 7.7 (6.6–8.8) |
| 3β5α-AP | 0.50 ± 0.12 | 15.3 | 0.51 ± 0.14 | 15.7 | >10,000 | >10,000 | >100 |
| THDOC | 2.32 ± 0.43 | 66.6 | 6.10 ± 0.68 | 183.0 | 410 | 760 | 5.0 (2.6–7.4) |
| ALFX | 1.31 ± 0.19 | 40.9 | 4.82 ± 0.53 | 144.6 | 990 | 1500 | 8.8 (6.1–11.4) |
| ORG-20599 | 3.10 ± 0.54 | 86.4 | 6.21 ± 0.42 | 186.3 | 120 | 310 | 18.6 (16.6–20.6) |
| AD | 0.86 ± 0.19 | 33.2 | 1.95 ± 0.29 | 49.9 | 1710 | 3120 | 44.0 (30.2–58.8) |