Affinity and efficacy of MRK-016 and major metabolites at GABAA receptor subtypes
| Human Recombinant GABAA Subtype | |||||
|---|---|---|---|---|---|
| α1 | α2 | α3 | α5 | ||
| MRK-016 (parent) | Affinity, nMa | 0.83 | 0.85 | 0.77 | 1.36 |
| Efficacy, %b | −16 | 6 | −9 | −55 | |
| M1 (aldehyde-aldehyde oxidase product) | Affinity, nM | 372 | N.D. | 578 | 700 |
| Efficacy, % | 1 | 0 | −8 | −39 | |
| M2 (tert-butyl hydroxylation) | Affinity, nM | 26 | N.D. | 9.8 | 9.4 |
| Efficacy, % | −41 | −23 | −32 | −40 | |
| M3 (isoxazole hydroxylation) | Affinity, nM | 1.5 | N.D. | 0.69 | 1.1 |
| Efficacy, % | −11 | −1 | −15 | −52 | |
N.D., not determined.
↵a Affinity was measured in human recombinant GABAA receptors using a competition [3H]flumazenil radioligand binding assay as described in detail under Materials and Methods.
↵b Efficacy was determined using whole-cell patch-clamp electrophysiology and was defined as the ability of a compound to decrease (negative values, inverse agonism) or increase (positive values, agonism) the current produced by the application of an EC20-equivalent concentration of GABA.