| 名稱 | Cebranopadol |
| 描述 | Cebranopadol (GRT6005) is an analgesic NOP and opioid receptor agonist with Kis of 0.9 nM, 0.7 nM, 2.6 nM, 18 nM for human NOP, μ-opioid (MOP), κ-opioid (KOP) and δ-opioid (DOP) receptor, respectively. |
| 激酶實驗 | Rat MOP, KOP, and NOP receptor binding assays were run using membrane suspensions from rat brain without the cerebellum for MOP receptors; without the pons, medulla oblongata, and cerebellum for NOP receptors; and without the pons, medulla oblongata, cerebellum, and cortex for KOP receptors and the following tritium-labeled radioligands: [3H]DAMGO in the MOP receptor assay, [3H]nociceptin in the NOP receptor assay, and [3H]Ci-977 in the KOP receptor assay. The assay buffer used for the binding studies was 50 mM Tris-HCl (pH 7.4) supplemented with 0.05% sodium azide. The final assay volume of 250 μl/well included 2 nM [3H]DAMGO, 1 nM [3H]nociceptin, or 1 nM [3H]Ci-977 as a ligand in the MOP, NOP, or KOP receptor assays, respectively, and cebranopadol in dilution series. Cebranopadol was diluted with 25% DMSO in water to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. The assays were started by the addition of the membrane suspensions and, after short mixing, the assays were run for 90 minutes at room temperature. All incubations were run in triplicate and terminated by rapid filtration under mild vacuum and two washes of 5 ml of buffer using FP-100 Whatman GF/B filter mats. The radioactivity of the samples was counted after a stabilization and extraction period of at least 15 hours by use of the scintillation fluid Ready Protein; the complete competition curves for cebranopadol were recorded [1]. |
| 動物實驗 | The pharmacokinetic properties of cebranopadol in rats were investigated after a single intravenous dose of 160 μg/kg cebranopadol. The intravenous dose was administered as a bolus in a volume of 2 ml/kg with a catheter in the vena femoralis. Blood samples (200 μl/sample) were withdrawn via an implanted arterial catheter (arteria carotis) by an automated blood sampling system at the following sampling times: 0 (predose), 5, 15, 30, 60, 180, 360, 720, and 1440 minutes after administration. Blood samples were centrifuged, and plasma was separated. Plasma concentrations of cebranopadol were determined using a validated liquid chromatography-tandem mass spectrometry method. The lower limit of quantification for cebranopadol in this method was 0.05 ng/ml using a sample volume of 50 μl of plasma [1]. |
| 體外活性 | Cebranopadol在人類MOP和DOP受體上展示了完全激動劑效能，在人類NOP受體上展現(xiàn)了近乎完全的效能，并在人類KOP受體上表現(xiàn)了部分效能。在使用表達(dá)人類5-HT5A受體的膜進(jìn)行的功能性[35S]GTPgS結(jié)合實驗中，Cebranopadol在高達(dá)10.0 μM的濃度下既未顯示激動劑效應(yīng)也未表現(xiàn)出顯著的拮抗效應(yīng)[1]。 |
| 體內(nèi)活性 | Cebranopadol在多種大鼠急性和慢性痛模型中顯示出高效和高效能的抗痛覺過敏和抗高敏感性效果，經(jīng)靜脈注射后的ED50值為0.5-5.6μg/kg，口服后為25.1μg/kg。Cebranopadol的作用持續(xù)時間長（靜脈注射12μg/kg后達(dá)7小時；口服55μg/kg后在大鼠尾巴抽動測試中超過9小時）[1]。在streptozotocin（STZ）處理的大鼠中，Cebranopadol（i.pl.）減輕了同側(cè)爪的機械性高敏感，但在對側(cè)爪無效果。在CCI大鼠中，Cebranopadol（i.pl.）在同側(cè)爪顯示出抗痛覺喪失活性。向?qū)?cè)爪注射后，Cebranopadol也展現(xiàn)了同側(cè)的抗痛覺喪失活性，但效力降低且起效延遲。在糖尿病小鼠中，Cebranopadol i.th.和i.c.v.以完全有效性和類似的效力減少了熱性高痛敏感性[2]。在NOP(-/-)小鼠中，嗎啡處理產(chǎn)生了與NOP(+/+)動物相同的撤藥癥狀，而Cebranopadol處理在NOP(-/-)小鼠中引起了比NOP(+/+)小鼠更強烈的撤藥綜合癥[3]。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 5 mg/mL (13.21 mM), Sonication is recommended.
H2O : Insoluble
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| 關(guān)鍵字 | Inhibitor | inhibit | Opioid Receptor | GRT-6005 | Cebranopadol | GRT 6005 |
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