GPR88 agonist
BI-9508
BI-9508 is a potent and selective agonist of the orphan central nervous system (CNS) receptor GPR881. Lacking the primary amine associated with high P-glycoprotein (PGP) efflux of other GPR88 agonists reported to date, it displays good brain permeability properties, rendering it suitable for in vitro and in vivo studies. The closely related compound BI-0823 is available as a negative control.
More information
GPR88 is an orphan G protein-coupled receptor (GPCR) primarily expressed and widely distributed in the GABAergic medium spiny neurons of the striatum1. Its presence has also been confirmed in other brain regions such as the cerebral cortex, amygdala, and hypothalamus2. The striatum itself is composed of the dorsal caudate putamen and the ventral nucleus accumbens. The former controls motor responses and is also involved in the compulsive behaviors associated with drug abuse, whereas the latter is the main center for reward and motivation behaviors, including drug and food reward3.
GPR88 knockout mice demonstrate altered motor coordination, increased sensitivity to rewarding stimuli, and increased anxiety-like behavior5. Additionally, GPR88 gene expression can be modulated by anti-depressant pharmacological interventions, as well as by physiological neurotransmitters such as glutamate and dopamine6. Overall, the research to date suggests that GPR88 may contribute to processes like locomotion, learning, emotional reactions, and social interactions, and may play a pivotal role in neurological operations3,6.
As the endogenous ligand of GPR88 is unknown, upregulation of its function requires the use of either agonists or positive allosteric modulators (PAMs)7,8. BI-9508 is a brain-penetrant molecule lacking the primary amine associated with high P-glycoprotein (PGP) efflux of other GPR88 agonists reported to date. The in vivo PK properties of BI-9508 render it a useful tool compound to elucidate the intracellular signaling mechanisms and physiological functions of GPR88.
Model of the complex of GPR88 with BI-9508, based on 7EJX.pdb10
BI-9508 displays an EC50 of 47 nM in a Gi1 BRET assay with human GPR88 (hGPR88) over-expressing HEK293 cells.
| Probe name / negative control | BI-9508 | BI-0823 |
| MW [Da]a | 521.6 | 374.3 |
| hGPR88 Gi1 BRET assay (EC50) [nM]b | 47 | >99,999 |
aFor the salt for you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
bAssay conditions: hGPR88 Gi1 BRET assay
The hGPR88 Gi1 BRET assay is based on transiently transfected HEK293 cells with unmodified human GPR88 receptor and a biosensor consisting of the sub-domain of the Gi/o protein-effector protein Rap1GAP fused to Renilla luciferase (RlucII) and co-expressed with the alpha subunit of Gi1 protein11. Upon receptor activation, the energy effector translocates to the plasma membrane to bind activated Gα protein. This interaction brings RlucII in close proximity to the energy acceptor, Renilla green fluorescent protein (rGFP), targeted to the plasma membrane through a CAAX motif (rGFP-CAAX), thus leading to an increase in BRET signal. Compounds were tested in a dose responsive manner using 20 concentrations, ranging from 100 μM to 0.003 μM, in 384 well micro titer plates. 2-PCCA had been used as positive control for receptor activation11.
BI-9508 shows good in vitro MDCK permeability and low efflux. Its metabolic stability is acceptable for acute rodent studies.
| Probe name / negative control | BI-9508 | BI-0823 |
| logD @ph 2 / 11 | 4.3 / 4.4 | 1.6 / 1.8 |
| Solubility @ pH 6.8 [µg/mL] | <1 | >75 |
| MDCK permeability PappAP @ 1µM [10-6 cm/s] | 31 | n.a. |
| MDCK efflux ratio | 1.1 | n.a. |
| Microsomal stability (human/mouse/rat) [% QH] | 45 / 40 / 69 | 77 / >88 / 85 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 50 / 60 / n.a. | n.a. |
| Plasma Protein Binding (human/mouse/rat) [%] | 98.6 / 99.1 / 98.5 | n.a. |
| hERG (IC50) [µM] | 5.1 | n.a. |
| CYP 3A4 (IC50) [µM] | >50 | 4 |
| CYP 2C8 (IC50) [µM] | >50 | 18 |
| CYP 2C9 (IC50) [µM] | >50 | >50 |
| CYP 2C19 (IC50) [µM] | >50 | >50 |
| CYP 2D6 (IC50) [µM] | >50 | >50 |
BI-9508 shows an acceptable in vivo profile for acute rodent studies.
BI-9508 | Mouse |
| Clearance [% QH]a | 34.6 |
| Mean residence time after iv dose [h]a | 2.9 |
| tmax [h]b,c | 0.42 / 0.19 |
| Cmax [nM]b,c | 140.0 / 388.3 |
| F [%] | 26 / 35 |
| Vss [l/kg] | 5.4 |
ai.v. dose: 0.5 mg/kg
bp.o. dose: 5 mg/kg
ci-periton. dose: 1 mg/kg
BI-0823 is similar in structure to BI-9508 as it contains the OCF2, cyclopropyl amide, and aryl substitution patterns. Due to the lack of an additional aryl group that is essential for agonist activity on GPR88, BI-0823 serves as a good negative control.
BI-0823 which serves as a negative control
Selectivity data available | BI-9508 | BI-0823 |
SafetyScreen44™ with kind support of  | Yes | Yes |
Download selectivity data:
BI-9508_selectivityData.xlsx
BI-0823_selectivityData.xlsx
BI-9508 is a potent agonist of the G-protein-coupled receptor 88 (GPR88). Its selectivity profile and good brain penetration properties compared to earlier agonists, render it suitable for in vitro and in vivo studies.
Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies
Fer M., Amalric C., Arban R., Baron L., Ben Hamida S., Breh-Schlanser P., Cui Y., Darcq E., Eickmeier C., Faye V., Franchet C., Frauli M., Halter C., Heyer M., Hoenke C., Hoerer S., Hucke O. T., Joseph C., Kieffer B. L., Lebrun L., Lotz N., Mayer S., Omrani A., Recolet M., Schaeffer L., Schann S., Schlecker A., Steinberg E., Viloria M., Würstle K., Young K., Zinser A., Montel F., Klepp J.
J. Med. Chem. 2024, 67, 11296–11325.
Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats
Ingallinesi M., Bouil L-L, Biguet N. F., Thi A.D., la Cour C. M., Millan M. J., Ravassard P., Mallet J., Meloni R.
Mol. Psychiatr. 2015, 20, 951–958.
Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing
Ehrlich A. T., Semache M., Bailly J., Wojcik S., Arefin T. M., Colley C., Gouill C. L., Gross F., Lukasheva V., Hogue M., Darcq E., Harsan L.-A., Bouvier M., Kieffer B. L.
Brain Struct. Funct. 2018, 223, 1275–1296.
The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders?
Logue S. F., Grauer S. M., Paulsen J., Graf R., Taylor N., Sung M. A., Zhang L., Hughes Z., Pulito V. L., Liu F., Rosenzweig-Lipson S., Brandon N. J., Marquis K. L., Bates B., Pausch M.
Mol. Cell. Neurosci. 2009, 42, 438–447.
Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs
Avet C., Mancini A., Breton B., Gouill C. L., Hauser A. S., Normand C., Kobayashi H., Gross F:, Hogue M., Lukasheva V., St-Onge S., Carrier M., Héroux M., Morissette S., Fauman E. B., Fortin J.-P., Schann S., Leroy X., Gloriam D. E., Bouvier M.
eLife. 2022, 11, e74101.
When you plan a publication, please use the following acknowledgement:
BI-9508 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.