| 名稱 | Bitopertin |
| 描述 | Bitopertin (Paliflutine) (RG1678, RO-4917838) is a potent inhibitor of glycine transporter 1 (GlyT1), with Ki of 8.1 nM for human hGlyT1b and IC50 of 22-25 nM in Chinese hamster ovary cells. |
| 激酶實(shí)驗(yàn) | 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]. |
| 動(dòng)物實(shí)驗(yàn) | Bitopertin (RG1678) is dissolved in H2O with 0.3% Tween 80 (Mice)[1]. Bitopertin (RG1678) is prepared in Polysorbate 80, HEC, Methyl- and Propylparaben pH 6.0 (Rats)[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. 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. |
| 體外活性 | RG1678在穩(wěn)定表達(dá)hGlyT1b和mGlyT1b的細(xì)胞中非競(jìng)爭(zhēng)性抑制[3H]甘氨酸的攝取，其IC50值分別為25 ± 2 nM和22 ± 5 nM（n = 6），并在來(lái)自中國(guó)倉(cāng)鼠卵巢細(xì)胞的膜上以8.1 nM的Ki值競(jìng)爭(zhēng)性置換[3H]ORG24598的結(jié)合，針對(duì)human hGlyT1b。至30 μM濃度，RG1678對(duì)hGlyT2介導(dǎo)的[3H]甘氨酸攝取無(wú)影響?；谥脫Q[3H]ORG24598的能力，RG1678的藥理學(xué)在不同物種之間沒(méi)有顯著差異。在海馬CA1錐體細(xì)胞中，RG1678在30 nM（213 ± 18%；n=7）、100 nM（269 ± 44%，n=13）時(shí)增強(qiáng)NMDA依賴的長(zhǎng)期增強(qiáng)效應(yīng)（LTP），但在300 nM（152 ± 14%；n=9）時(shí)則沒(méi)有這種效果。 |
| 體內(nèi)活性 | 給予RG1678后，在大鼠的微透析實(shí)驗(yàn)和大鼠的腦脊液(CSF)中均可觀察到持續(xù)時(shí)間超過(guò)3小時(shí)的劑量依賴性胞外甘氨酸水平增加。在小鼠中，RG1678劑量依賴性且顯著地減輕了由精神興奮劑D-安非他明引起的過(guò)度活動(dòng)。此外，RG1678還能阻止長(zhǎng)期用苯環(huán)已哌啶（一種NMDA受體開(kāi)放通道阻斷劑）處理的大鼠對(duì)D-安非他明挑戰(zhàn)的過(guò)度反應(yīng)[1]。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 50 mg/mL (92 mM)
H2O : Insoluble
Ethanol : 5 mg/mL
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| 關(guān)鍵字 | inhibit | Bitopertin | GlyT | Inhibitor | RO 4917838 | RG-1678 | RG 1678 | Glycine transporters | RO-4917838 |
| 相關(guān)產(chǎn)品 | Opiranserin | ALX-1393 | Bitopertin (R enantiomer) | Org 25543 hydrochloride | Opiranserin hydrochloride | PF-03463275 | Tilapertin | Amoxapine | Sarcosine | Iclepertin | ASP2535 | LY2365109 hydrochloride |
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