2. Membrane Transporter/Ion Channel Neuronal Signaling
  3. GlyT
  4. Bitopertin

Bitopertin  (Synonyms: RG1678; RO4917838)

Cat. No.: HY-10809 Purity: 99.59%
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Bitopertin is a potent, noncompetitive glycine reuptake inhibitor, inhibits glycine uptake at human GlyT1 with a concentration exhibiting IC50 of 25 nM.

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Bitopertin Chemical Structure

Bitopertin Chemical Structure

CAS No. : 845614-11-1

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Based on 1 publication(s) in Google Scholar

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Bitopertin Related Antibodies

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GlyT1 GlyT2

  • Biological Activity

  • Protocol

  • Purity & Documentation

  • References

  • Customer Review

Description

Bitopertin is a potent, noncompetitive glycine reuptake inhibitor, inhibits glycine uptake at human GlyT1 with a concentration exhibiting IC50 of 25 nM.

IC50 & Target

GlyT1

 

In Vitro

Bitopertin (RG1678) competitively blocks [3H]ORG24598 binding sites at human GlyT1b in membranes from Chinese hamster ovary cells. Bitopertin potently inhibits [3H]glycine uptake in cells stably expressing hGlyT1b and mGlyT1b, with IC50 values of 25±2 nM and 22±5 nM, respectively (n=6). Conversely, Bitopertin has no effect on hGlyT2-mediated glycine uptake up to 30 μM concentration. Bitopertin has high affinity for the recombinant hGlyT1b transporter. Under equilibrium conditions (1 h at room temperature), Bitopertin displaces [3H]ORG24598 binding with a Ki of 8.1 nM. In hippocampal CA1 pyramidal cells, Bitopertin enhances NMDA-dependent long-term potentiation at 100 nM but not at 300 nM[1]. Additional profiling revealed that Bitopertin (RG1678) has an excellent selectivity profile against the GlyT2 isoform (IC50>30 μM) and toward a panel of 86 targets including transmembrane and soluble receptors, enzymes, ion channels, and monoamine transporters (<41% inhibition at 10 μM is measured for all targets)[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Bitopertin Related Antibodies
In Vivo

Bitopertin (RG1678) dose-dependently increases cerebrospinal fluid and striatal levels of glycine measured bymicrodialysis in rats. Additionally Bitopertin attenuates hyperlocomotion induced by the psychostimulant D-amphetamine or the NMDA receptor glycine site antagonist L-687,414 in mice. Bitopertin also prevents the hyper-response to D-amphetamine challenge in rats treated chronically with phencyclidine, an NMDA receptor open-channel blocker. Administration of vehicle has no effect on extracellular levels of striatal glycine, which remained constant throughout the experiment. In contrast, p.o. administration of Bitopertin (1-30 mg/kg) produced a dose-dependent increase in extracellular glycine levels. Bitopertin 30 mg/kg produces glycine levels 2.5 times higher than pretreatment levels. A similar dose-dependent increase in glycine concentration is observed in the CSF of rats treated p.o. with Bitopertin (1-10 mg/kg) compared with vehicle-treated animals, 3 h after drug administration. Interestingly, the level of CSF glycine increase 3 h after Bitopertin dosing is very similar to the increase in the microdialysis experiment at the same time point[1]. In vivo pharmacokinetic studies in rat and monkey reveals that Bitopertin (RG1678) has, in both species, a low plasma clearance, an intermediate volume of distribution, a good oral bioavailability (78% for rat, 56% for monkey), and a favorable terminal half-life (5.8 h for rat, 6.4 h for monkey). The plasma protein binding is high in the two preclinical species (97%) and in human (98%). The CNS penetration of Bitopertin in rat (brain/plasma=0.7) is better than that in mouse (brain/plasma=0.5)[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
Molecular Weight

543.46

Formula

C21H20F7N3O4S
CAS No.
Appearance

Solid

Color

White to off-white

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
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 2 years
-20°C 1 year
Solvent & Solubility
In Vitro: 

DMSO : ≥ 50 mg/mL (92.00 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

*"≥" means soluble, but saturation unknown.

Preparing
Stock Solutions
Concentration Solvent Mass 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
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

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Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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Molecular Weight *

Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2

Concentration (start)

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In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

    Solubility: ≥ 2.5 mg/mL (4.60 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

    Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% Corn Oil

    Solubility: ≥ 2.5 mg/mL (4.60 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL Corn oil, and mix evenly.

In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

Dosage

mg/kg

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(per animal)

g

Dosing volume
(per animal)

μL

Number of animals

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
DMSO +
% 
+
%
Tween-80 +
%
Saline
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation

Purity: 99.59%

SDS (252 KB)

COA (249 KB) LCMS (105 KB)

Handling Instructions (2659 KB)
References
Kinase Assay
[1]

Association and dissociation kinetic analysis of [3H]ORG24598 to hGlyT1 and ratforebrain membranes is performed. [3H]ORG24598 binding experiments are performed using membranes from CHO cells expressing hGlyT1b and also in membranes from mouse, rat, monkey, and dogforebrains. Saturation isotherms are determined by adding [3H]ORG24598 to rat, mouse, monkey, and dog forebrain membranes (40 μg/well) and cell membranes (10 μg/well) in a total volume of 500 μL for 3 h at room temperature. Saturation binding experiments are analyzed by an Excel-based curve-fitting program using the Michaelis-Menten equation derived from the equation of a bimolecular reaction and the law of mass action:B=(Bmax×[F])/(Kd+[F]), where B is the amount of ligand bound at equilibrium, Bmax the maximum number of binding sites, [F] the concentration of free ligand, and Kd the ligand dissociation constant. For inhibition experiments, membranes are incubated with 3 nM [3H]ORG24598 and 10 concentrations of Bitopertin for 1 h at room temperature. Schild analysis is performed in the presence of increasing concentrations of [3H]ORG24598 (1-300 nM). IC50 values are derived as described above. Ki values are calculated according to the following equation: Ki=IC50/(1+[L]/Kd)[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration
[1]

Mice[1]
Male NMRI mice (20-30 g) are treated with Bitopertin (0.3, 3, 1, and 10 mg/kg p.o.) or vehicle (p.o.). After 1 min, L-687,414 (50 mg/kg s.c.) or vehicle is given. After 15 min of habituation in the activity chambers, horizontal activity is recorded for 60 min. The time course of Bitopertin effects on L-678,414-induced hyperactivity is also examined; locomotor activity is assessed 2.5, 4.5, and 24 h after administration of Bitopertin (L-678,414 is always given 15 min before the activity procedure). In addition, the effect of subchronic Bitopertin is investigated. Mice receive vehicle or Bitopertin (1 mg/kg p.o.) for 4 consecutive days and L-678,414-induced hyperactivity is evaluated on day 5.
Rats[1]
Wistar rats receive a 14-day treatment of PCP HC1 (5 mg/kg) or vehicle (NaCl 0.9%, 5 mL/kg i.p.). 24 h following the last injection, rats (6-18 per group) are allowed to individually habituate to the test boxes for 30 min. Rats then received Bitopertin (1, 3, 10 mg/kg p.o.) or vehicle (Polysorbate 80, HEC, Methyl- and Propylparaben pH 6.0; 5 mL/kg p.o.), followed after 1 h by 1 mg/kg D-amphetamine or vehicle i.p. Horizontal activity is recorded directly after the administration of Bitopertin until 120 min after dosing with amphetamine. Data are analyzed by ANOVA supplemented by Fischer's least significant difference post hoc test.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.8401 mL 9.2003 mL 18.4006 mL 46.0015 mL
5 mM 0.3680 mL 1.8401 mL 3.6801 mL 9.2003 mL
10 mM 0.1840 mL 0.9200 mL 1.8401 mL 4.6002 mL
15 mM 0.1227 mL 0.6134 mL 1.2267 mL 3.0668 mL
20 mM 0.0920 mL 0.4600 mL 0.9200 mL 2.3001 mL
25 mM 0.0736 mL 0.3680 mL 0.7360 mL 1.8401 mL
30 mM 0.0613 mL 0.3067 mL 0.6134 mL 1.5334 mL
40 mM 0.0460 mL 0.2300 mL 0.4600 mL 1.1500 mL
50 mM 0.0368 mL 0.1840 mL 0.3680 mL 0.9200 mL
60 mM 0.0307 mL 0.1533 mL 0.3067 mL 0.7667 mL
80 mM 0.0230 mL 0.1150 mL 0.2300 mL 0.5750 mL
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Bitopertin Related Classifications

Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

Bitopertin845614-11-1RG1678 RO4917838RG 1678RG-1678RO4917838RO 4917838RO-4917838GlyTGlycine transportersInhibitorinhibitorinhibit

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