GABAA alpha5 | BI-1030
Highlights
GABA type A receptor subtypes containing alpha5 subunits are of particular research interest due to their specific brain distribution, unusual surface localization and key roles in synaptic plasticity, cognition and memory. Only a few molecules in the literature are showing subtype selectivity for GABAA alpha5 receptors and Boehringer Ingelheim in collaboration with Saniona A/S, have designed a very potent, selective, and in vivo ready GABAA alpha5 functionally selective negative allosteric modulator (NAM), BI-1030.
Background information
Target Information
The gamma-aminobutyric acid (GABA) type A receptors (GABAARs) are heteropentameric ligand-gated chloride ion (Cl−) channels typically composed of two alpha (alpha1–6), two beta (beta 1–3), and one gamma (gamma 1–3) or delta subunits1. Binding of the neurotransmitter GABA opens an intrinsic ion channel that permits the passage of chloride ions and drives inhibitory neurotransmission in the mammalian central nervous system. GABAARs play critical roles in the central nervous system (CNS) implying neuronal plasticity, and drugs targeting GABAARs show diverse central pharmacology2. Alpha 5-containing GABAARs in particular, are highly expressed in both the hippocampus and olfactory bulb. Characteristically, alpha 5 GABAARs comprise close to 25% of all hippocampal GABAARs, and over a third of the neurons in the internal granule cell layer of the olfactory bulb1.
Model of the complex of BI-1030 bound to the interface of the alpha5 and the gamma2 GABAA receptor subunits (only extracellular domains shown).
In vitro activity
BI-1030 displays a Ki of 57 nM on the GABAA alpha5 receptor, and it is functionally selective for the GABAA receptor subtypes alpha1, alpha2, and alpha3 .
Probe name / negative control | BI-1030 |
| MW [Da] | 364 |
| GABAA alpha5 Bdg (Ki) [nM]a | 57.1 |
| GABAA alpha5 EPHys (EC50) [nM]b | 114.4 |
| GABAA alpha5 EPHys (Emax) [%]b | -28.5 |
| GABAA alpha1 EPHys (EC50) [nM]b | - |
| GABAA alpha1 EPHys (Emax) [%]b | -2.8 |
| GABAA alpha2 EPHys (EC50) [nM]b | - |
| GABAA alpha2 EPHys (Emax) [%]b | -4.3 |
| GABAA alpha3 EPHys (EC50) [nM]b | - |
| GABAA alpha3 EPHys (Emax) [%]b | 0.8 |
| GABAA alpha1 Bdg (Ki) [nM]a | 1,100 |
| GABAA alpha4 Bdg (Ki) [nM]a | 14,000 |
| GABAA alpha6 Bdg (Ki) [nM]a | >14,000 |
a In vitro inhibition of 3H-flumazenil binding HEK cells expressing the human GABAA alpha5-beta3-gamma2. Details of the experiment can be found in reference 3.
b Modulatory efficacy on GABAA subtypes is determined by electrophysiological recordings in oocytes using the two-electrode voltage clamp (TEVC) technique. Oocytes are injected with cRNA for human GABAA receptor subunits. Details of the experiment can be found in references 3 and 4.
In vitro DMPK and CMC parameters
BI-1030 presents good in vitro DMPK and CMC properties, being soluble and metabolically stable.
Probe name / negative control | BI-1030 |
| logP/logD (@pH 2.0/11.0) | 1.4/ (-/-) |
| Solubility @ pH 6.8 [µg/ml] | 0.01 |
| MDCK permeability Pappa-b/b-a @ 1µM [10-6 cm/s] | 45 |
| MDCK efflux ratio | 1.1 |
| Microsomal stability (human/mouse/rat/dog/MP) [% QH] | <23 / <23 / <22 / <20 / <23 |
| Hepatocyte stability (human/mouse/rat/dog) [% QH] | 10/ 21 / 6 / 34 |
| Plasma protein binding (human/mouse/rat/dog/MP) [%] | 65 / 59 / 52 / 55 / 67 |
| hERG KI [µM] | >10 |
| CYP 3A4 (IC50) [µM] | >25 |
| CYP 2C8 (IC50) [µM] | >50 |
| CYP 2C9 (IC50) [µM] | >25 |
| CYP 2C19 (IC50) [µM] | >25 |
| CYP 2D6 (IC50) [µM] | >25 |
In vivo DMPK parameters
BI-1030 is stable in different species, with an excellent bioavailability allowing its use in vivo.
BI-1030 | Mousea | RATb | Dogc |
| Clearance [% QH] | 6.6 | 5.7 | 25 |
| Mean residence time after iv dose [h] | 2.6 | 3.3 | 2.7 |
| tmax [h] | 0.7 | 4 | 1.3 |
| Cmax [nM] | 495 | 354 | 225 |
| F [%] | 100 | 65 | 64 |
| Vss [l/kg] | 0.9 | 0.8 | 1.3 |
a 0.4 mg/kg iv and 1.8 mg/kg po
b 0.4 mg/kg iv dose [mg/kg] 3.6 mg/kg po
c 0.4 mg/kg iv dose [mg/kg] 3.6 mg/kg po
In vivo pharmacology
BI-1030 shows a very favorable in vivo profile in different CNS in vivo models showing that the GABAA alpha5 NAM is a reliable mode of action to potentially address complex central disease mechanisms.
BI-1030 attenuates sub-chronic phencyclidine (PCP)-induced impairment in novel object recognition tasks in rats, indicating potential beneficial effects on episodic memory.
X: BI-1030: 1, 3, 10 mg/kg, po, t= -60 minutes
Y: RO4938581: 1, 3 mg/kg, po, t= -60 minutes
PCP: 2 mg/kg, i.p. BID 7 days on/7 days off prior to behavioral testing
Rats: female Lister hooded rats
Data produced by Grayson B. and Neill J., b-neuro, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester, UK, 2016.
Selectivity
BI-1030 displays a Kialpha of 57 nM on the GABAA alpha5 receptor, and it is functionally selective for subtypes alpha1, alpha2, and alpha3. It is otherwise also clean in the SafetyScreen profile from Eurofins.
Selectivity data available | BI-1030 |
SafetyScreen44™ with kind support of  | Yes |
| Invitrogen® | No |
| DiscoverX® | No |
| Dundee | No |
Download selectivity data:
BI-1030_selectivityData.xlsx
Summary
GABA type A receptors are chloride ion channels that drive inhibitory neurotransmission in the mammalian central nervous system upon binding of GABA, the primary inhibitory neurotransmitter in the central nervous system. BI-1030 is a potent and functionally selective GABAA alpha5 receptor negative allosteric modulator (NAM), suitable for in vitro as well as in vivo use.
Supplementary data
2 D structure formats available
Reference molecule
Basmisanil (RG1662, Cas No.:1159600-41-5)5, a highly selective GABAA alpha5 negative allosteric modulator.
References
The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors
Kasaragod V. B., Malinauskas T., Wahid A. A., Lengyel J., Knoflach F., Hardwick S. W., Jones C. F., Chen W. N., Lucas X., Omari K. E., Chirgadze D. Y., Aricescu A. R., Cecere G., Hernandez M. C., Miller P. S.
Nat. Struct. Mol. Biol. 2023. 30, 1936–1946.
Diflurormethyl-Phenyl Triazoles as GABA Receptor Modulators EPO
Larsen, J., Binder, F., Cui, Y., Hucke, O., Lipinski, R., Montel, F., Ostermeier, M., Perera, A., Peters, S.
European publication server 2020. WO2020/016443.
NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABAA Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy
Mirza N.R., Larsen J.S., Mathiasen C., Jacobsen T.A., Munro G., Erichsen H.K., Nielsen A.N., Troelsen K.B., Nielsen E.O., Ahring P.K.
J. Pharmacol. Exp. Ther. 2008. 327, 954-968.
Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man.
Hipp J. F., Knoflach F., Comley R., Ballard T. M., Honer M., Trube G., Gasser R., Prinssen E., Wallace T. L., Rothfuss A., Knust H., Lennon-Chrimes S., Derks M., Bentley D., Squassante L., Nave S., Nöldeke J., Wandel C., Thomas A. W., Hernandez M. C.
Sci. Rep. 2021. 11, 7700.
How to cite opnMe?
When you plan a publication, please use the following acknowledgement:
BI-1030 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
