Potency and maximal efficacy of test compounds at α1β1γ2 or α1β2γ2 GABAARs in rank order of ascending efficacy at α1β1γ2
The mouse RR AD50 value is provided for each compound if determinable over the range of doses tested. The peak brain levels associated with the AD50 or the highest doses tested, when an AD50 could not be attained, are expressed in micromolar. In vitro potency is expressed as the EC50 (micromolar) followed by its 95% confidence interval in parentheses, and maximal efficacy is expressed as the percentage of modulation of an EC10 GABA effect. Brain levels are expressed as the mean ± S.E.M. (n = 3–9). All test compounds were administered by intraperitoneal injection except for 2-261, 2-262, and mefenamic acid, which were administered orally.
| Compound | Maximal Efficacy at α1β1γ2 | EC50 at α1β2γ2 | Maximal Efficacy at α1β2γ2 | EC50 at α1β2γ2 | RR AD50 | Brain Level |
|---|---|---|---|---|---|---|
| % | μM | % | μM | mg/kg | μM | |
| L-838,417a | 0 | N.D. | 0 | N.D. | 30 | 8 ± 1 |
| 2-325 | 16 | N.D. | 1330 | 0.22 (0.1–4.6) | >30 | 2.1 ± 0.4 |
| Mefenamic acid | 18 | N.D. | 315 | 3.6 (2.5–5.1) | >500 | 3.1 ± 0.7 |
| 2-313 | 33 | N.D. | 727 | 0.14 (0.09–0.2) | >50 | 1.2 ± 0.1 |
| 2-261 | 34 | N.D. | 1101 | 0.3 (0.1–0.6) | >100 | 3.7 ± 0.5 |
| 2-301 | 47 | N.D. | 686 | 0.22 (0.1–0.7) | >100 | 4.0 ± 1.5 |
| Ocinaplon | 81 | 2.8 (0.7–11) | 72 | 2.1 (0.3–19) | 54 | 12.5 ± 1.5 |
| Bretazenil | 95 | 0.05 (0.01–0.42) | 58 | 0.004 (0.001–0.008) | 25 | 11.7 ± 3.0 |
| Diazepam | 109 | 0.11 (0.03–0.5) | 166 | 0.05 (0.02–0.1) | 2 | 0.64 ± 0.3 |
| 2-128 | 113 | 2.4 (1.2–4.9) | 552 | 0.9 (0.6–1.3) | >120 (40% failure at 120) | 5.8 ± 2.0 |
| Loreclezole | 125 | 40 (31–52) | 498 | 4.8 (3.1–7.5) | 83 | 11.7 ± 3.2 |
| 2-262 | 181 | 1.4 (0.7–2.7) | 1102 | 0.04 (0.02–0.09) | 43 | 0.8 ± 0.3 |
| 2-249 | 249 | 3.6 (1.4–9.5) | 905 | 0.03 (0.01–0.1) | 3 | 0.6 ± 0.1 |
| 2-148 | 369 | 6.9 (3–12) | 817 | 0.2 (0.1–0.4) | 5 | 1.1 ± 0.1 |
| Tracazolate | 375 | 4.7 (2–12) | 821 | 0.6 (0.3–1.3) | 42 | 7.6 ± 1.7 |
| 2-314 | 655 | 0.2 (0.1–0.4) | 814 | 0.11 (0.03–0.4) | 2.5 | 0.30 ± 0.06 |
| Etomidate | 819 | 18 (12–27) | 1307 | 2 (1–8) | N.D. | N.D. |
N.D., not determined.
↵a L-838,417 is inactive at both α1-containing subtypes because of selectivity for α2/3- over α1-subunits.