RO4938581

RO4938581 : Negative Allosteric Modulator of GABRA5

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(1 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Probe RO4938581 is in the process of SERP review.

Please continue to check back for new reviews and commentary.

Information

GABRA5

Negative Allosteric

up to 1 uM

Additional Data

SGC image SGC Chemical Probe Collection

In Vitro Validations

Uniprot ID: P31644

Target Class: Ion Channel

Target SubClass: --

Potency: Ki

Potency Value: 4.65 ± 0.79 nM

Potency Assay: Radioligand competition displacement assay (recombinant human GABAA subtypes expressed in HEK293 cells)

PDB ID for probe-target interaction (3D structure): 8BHS

Target aliases:

Gamma-aminobutyric acid receptor subunit alpha-5, ...

DOI Reference: 10.1016/j.bmcl.2009.08.053

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Selectivity within family: Radioligand 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

Probe Selectivity in Vitro:

Roche CEREP panel (82 targets) at 10 µM: clean; Kinase panel (468 kinases) at 10 µM: clean with closest off-target GRK4 (50 % inhibition)

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

RO4938581 is a highly potent and reasonably selective GABAA alpha5 inverse agonist with a full molecular profiling dataset. The SAR is described, and negative controls can be selected from the described examples. RO4938581 is providing a favorable GABAA subtype specificity and overall selectivity (CEREP), resulting in a cellular and in vivo behavior profile which is fully in-line with an inverse agonistic mode of action. In vivo PK profile and in vivo efficacy studies are presented, but time- and exposure-resolved PK/PD studies are missing. Altogether, RO4938581 is a high-quality probe for in-vitro and in vivo studies of the GABA alpha5 receptor.

(last updated: 27 Nov 2025 )