RO4938581
Probe criteria
| Inhibitor/agonist potency: goal is < 100 nM (IC50, Kd) | Surpasses criterion: [3H]flumazenil competition displacement assay (recombinant human GABAA subtypes expressed in HEK293 cells): GABRA5 (α5β3γ2) (human: Ki = 4.65 ± 0.79 nM (n=8), rat: Ki = 13.8 nM) |
| Selectivity within target family: > 30-fold | Surpasses criterion: [3H]flumazenil competition displacement assay: GABRA1 (α1β3γ2): rat (Ki = 174 ± 28 nM old assay; Ki = 384 nM new assay) ,human (Ki =198 ± 93 nM, n=9 new assay), GABAA2 (α2β3γ2): rat (Ki = 185 ± 5nM old assay); human (Ki = 335 ± 26 nM, n=6, new assay), GABAA3 (α3β3γ2): rat (Ki = 79.6 ± 16 nM); >30-fold selectivity over the other GABAA subtypes |
| Selectivity outside target family | Surpasses criterion: Roche CEREP panel (82 targets) at 10 µM: clean; Kinase panel (468 kinases) at 10 µM: clean with closest off-target GRK4 (50 % inhibition) |
| On target cell activity for cell-based targets: goal is < 1 µM IC50/EC50 | Surpasses criterion: Electrophysiology (Whole cell patch-clamp in HEK293 cells expressing rat recombinant GABRA5 (α5β3γ2)): IC50 = 7.4 nM |
| Control compound (100 times less potent than the probe) | Surpasses criterion: RO4991571: [3H]flumazenil competition displacement assay (recombinant rat GABAA subtypes expressed in HEK293 cells): GABRA5 (α5β3γ2), GABRA1 (α1β3γ2): both Ki > 3.16 µM |