| Size | Price | Stock | Qty |
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| 5mg |
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| Other Sizes |
| Targets |
The primary target is glycine transporter 1 (GlyT1), a sodium- and chloride-dependent transporter that regulates glycine concentrations in the synaptic cleft. Bitopertin R enantiomer inhibits GlyT1 noncompetitively with an IC50 of 25 nM. This increases extracellular glycine levels, enhancing NMDA receptor co-agonism and glutamatergic neurotransmission. It shows selectivity for GlyT1 over GlyT2.
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| ln Vitro |
In the membrane of Chinese hamster ovary cells, bitopertin (RG1678) competitively blocks the [3H]ORG24598 binding site on human GlyT1b. Cells stably expressing hGlyT1b and mGlyT1b are efficiently inhibited from uptaking [3H]glycine by bitopertin, with IC50 values of 25±2 nM and 22±5 nM (n=6), respectively. Conversely, at doses as high as 30 μM, bitopertin exhibited no influence on hGlyT2-mediated glycine absorption. Bitopertin binds to the recombinant hGlyT1b transporter with a strong affinity. Bitopertin dispenses with [3H]ORG24598 binding under equilibrium conditions (one hour at room temperature) with a Ki of 8.1 nM. Bitopertin improved NMDA-dependent long-term potentiation in hippocampal CA1 pyramidal cells at 100 nM, but not at 300 nM [1]. Further investigation revealed that Bitopertin (RG1678) possesses exceptional selectivity for a panel of 86 targets, which includes soluble and transmembrane receptors, enzymes, ion channels, and monoamine transporters (IC50>30 μM) (Measurements for all targets are 10 μM) [2].
Bitopertin R enantiomer inhibits glycine uptake at human GlyT1 with an IC50 of 25 nM. It acts as a noncompetitive inhibitor, binding to the transporter at a site distinct from the glycine binding site. It potentiates NMDA receptor-mediated currents in electrophysiological assays. It shows high selectivity for GlyT1 over other neurotransmitter transporters. |
| ln Vivo |
Bitopertin (RG1678) elevates glycine levels in rat striatum and cerebrospinal fluid in a dose-dependent manner as determined by microdialysis. Furthermore, in mice stimulated with D-amphetamine or the NMDA receptor glycine site antagonist L-687,414, Bitopertin can reduce excessive movement. In rats receiving long-term phencyclidine treatment—an NMDA receptor open channel blocker—bitopertin also inhibits hyperresponsiveness to D-amphetamine stimulation. The extracellular levels of striatal glycine were unaffected by the vehicle and stayed unchanged during the experiment. Extracellular glycine levels, on the other hand, increased in a dose-dependent manner upon oral administration of Bitopertin (1–30 mg/kg). Glycine levels were 2.5 times greater after 30 mg/kg of biseptertin than they were before treatment. When comparing the CSF of rats given oral bitopertin (1–10 mg/kg) three hours after dosage to rats given a vehicle, a similar dose-dependent rise in glycine concentration was seen. Remarkably, the rise in glycine levels in the cerebrospinal fluid three hours following the administration of bitopertin was strikingly similar to the rise observed at the same time in microdialysis trials [1]. Bitopertin (RG1678) has been shown in in vivo pharmacokinetic tests conducted in rats and monkeys to exhibit low plasma clearance, a moderate distribution volume, and good oral bioavailability in both species (78% in rats and 56% in monkeys). Its terminal half-life (5.8 hours in rats and 6.4 hours in monkeys) is really good. In humans, 98%, and two preclinical species, 97%, plasma protein binding was observed. Rats (brain/plasma=0.7) have a higher rate of intrathecal penetration of betapertin than mice (brain/plasma=0.5) [2].
In vivo, bitopertin has been investigated in clinical trials for schizophrenia. The R enantiomer is the active form. In animal models, GlyT1 inhibition enhances prepulse inhibition and cognitive performance. Typical doses in rodent studies range from 0.1-10 mg/kg administered orally or intraperitoneally. Clinical trials showed mixed results for negative symptoms. |
| Enzyme Assay |
Glycine uptake assays use cells expressing recombinant human GlyT1 (CHO or HEK293 cells). Cells are incubated with [3H]glycine and the compound in assay buffer (Hanks' balanced salt solution, pH 7.4) at 37°C for 10-30 min. Uptake is terminated by washing, and radioactivity is quantified by scintillation counting. IC50 values are calculated from dose-response curves.
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| Cell Assay |
Cell-based assays for GlyT1 inhibition use primary neuronal cultures or GlyT1-expressing cell lines. Cells are treated with bitopertin R enantiomer (1 nM-10 µM) and [3H]glycine. Glycine uptake is measured by scintillation counting. NMDA receptor-mediated currents are measured using patch clamp electrophysiology in hippocampal slices or cultured neurons.
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| Animal Protocol |
In vivo, bitopertin is tested in rodent models of schizophrenia-like behaviors. A typical protocol involves oral administration (0.1-10 mg/kg) in rats or mice. Prepulse inhibition of acoustic startle, novel object recognition, and social interaction are assessed. Brain glycine levels are measured by microdialysis. Clinical trials evaluated doses of 5-30 mg/day in schizophrenia patients.
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| References |
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| Molecular Formula |
C₂₁H₂₀F₇N₃O₄S
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|---|---|
| Molecular Weight |
543.46
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| Exact Mass |
543.106
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| CAS # |
845614-12-2
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| Related CAS # |
Bitopertin;845614-11-1
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| PubChem CID |
49798777
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| Appearance |
White to off-white solid powder
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| LogP |
5.018
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
36
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| Complexity |
872
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=CC(C(F)(F)F)=CN=C1N2CCN(C(C3=CC(S(=O)(C)=O)=CC=C3O[C@@H](C(F)(F)F)C)=O)CC2
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| InChi Key |
YUUGYIUSCYNSQR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H20F7N3O4S/c1-12(20(23,24)25)35-17-4-3-14(36(2,33)34)10-15(17)19(32)31-7-5-30(6-8-31)18-16(22)9-13(11-29-18)21(26,27)28/h3-4,9-12H,5-8H2,1-2H3
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| Chemical Name |
[4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]-[5-methylsulfonyl-2-(1,1,1-trifluoropropan-2-yloxy)phenyl]methanone
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| Synonyms |
RO4917838 (R enantiomer; RG1678 (R enantiomer
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8401 mL | 9.2003 mL | 18.4006 mL | |
| 5 mM | 0.3680 mL | 1.8401 mL | 3.6801 mL | |
| 10 mM | 0.1840 mL | 0.9200 mL | 1.8401 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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