| 名稱 | ADL-5859 |
| 描述 | ADL-5859 (ADL5859 Hydrochloride) is a selective δ-opioid receptor agonist ( Ki: 0.8 nM), selectivity against opioid receptor κ, μ, and little inhibition for the hERG channel. |
| 細(xì)胞實(shí)驗(yàn) | Membrane preparations from Chinese hamster ovary (CHO) cells stably expressing human κ, μ, or δ opioid receptors are prepared. The assay buffer used is composed of 50 mMtris(hydroxymethyl) aminomethaneHCl, pH 7.8, 1.0 mM ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA free acid), 5.0 mM MgCl2 10 mg/L leupeptin, 10 mg/L pepstatin A, 200 mg/L bacitracin, and 0.5 mg/L aprotinin. After dilution in assay buffer and homogenization in a Polytron homogenizer for 30 seconds, membrane proteins (10-80 μg) in 250 μL of assay buffer are added to mixtures containing ADL5859 and [3H]diprenorphine (0.5-1.0 nM, 25000-50000 dpm) in 250 μL of assay buffer in 96-well deep-well polystyrene titer plates and incubated at room temperature for 60 minutes. Reactions are terminated by vacuum filtration with a Brandel MPXR-96T harvester through GF/B filters that have been pretreated with a solution of 0.5% polyethylenimine and 0.1% bovine serum albumin for at least 1 hour. The filters arewashed four times with 1.0 mL each of ice-cold 50 mM Tris-HCl, pH 7.8, and 30 μL of Microscint-20 is added to each filter. Radioactivity on the filters is determined by scintillation spectrometry in a Packard TopCount. [3H]Diprenorphine with a specific activity of 50 Ci/mmolisused. The Kd values for [3H]diprenorphine binding are 0.33 nM for the κ and μ receptors and 0.26 nM for the δ receptor. Receptor expression levels, determined as Bmax values from Scatchard analyses, are 4400, 4700, and 2100 fmol/mg of protein for the κ, μ, and δ receptors, respectively. Preliminary experiments are performed to show that no specific binding is lost during the wash of the filters, that binding achieved equilibrium within the incubation time and remained at equilibrium for at least an additional 60 minutes, and that binding is linear with regard to protein concentration. Nonspecific binding, determined in the presence of 10 μM unlabeled naloxone, is less than 10% of total binding.Protein is quantified by the method of Bradford. The data from competition experiments are fit by nonlinear regression analysis with the program Prism using the four-parameter equation for one-site competition, and Ki values are subsequently calculated from EC50 values by the Cheng-Prusoff equation.(Only for Reference) |
| 體外活性 | ADL5859是一種具有1000倍選擇性的δ-阿片受體激動(dòng)劑，在δ-阿片受體上的Ki值分別為32 nM和37 nM。ADL5859對(duì)hERG通道的抑制活性較弱，其IC50為78 μM。ADL5859針對(duì)δ阿片受體的EC50為20 nM。[1] |
| 體內(nèi)活性 | 在3 mg/kg口服劑量的篩選下, ADL5859能夠完全逆轉(zhuǎn)炎癥爪部的高敏反應(yīng)。ADL5859在FCA機(jī)械高敏反應(yīng)測(cè)定中的口服ED50為1.4 mg/kg。通過預(yù)處理δ阿片受體拮抗劑納曲酮（0.3 mg/kg皮下注射），ADL5859（3 mg/kg, 口服）產(chǎn)生的抗高敏效應(yīng)被逆轉(zhuǎn)，從而證明了δ受體介導(dǎo)的效應(yīng)。在大鼠強(qiáng)迫游泳試驗(yàn)中，ADL5859（3 mg/kg口服）產(chǎn)生顯著的抗抑郁樣活動(dòng)，表現(xiàn)為顯著減少靜止時(shí)間并顯著增加游泳時(shí)間。ADL5859（3 mg/kg口服）在大鼠和狗中的生物利用度分別為33％和66％。ADL5859通過招募外周Nav1.8表達(dá)神經(jīng)元所表達(dá)的δ-阿片受體，高效減輕炎癥性及神經(jīng)病理性疼痛。 |
| 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 | H2O : 5 mg/mL (11.65 mM)
DMSO : 35 mg/mL (81.59 mM), Sonication is recommended.
Ethanol : 1 mg/mL (2.33 mM)
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| 關(guān)鍵字 | inhibit | ADL5859 | ADL 5859 | Opioid Receptor | Inhibitor | ADL 5859 Hydrochloride | ADL-5859 Hydrochloride | ADL-5859 |
| 相關(guān)產(chǎn)品 | Docusate sodium | Progesterone | Naltrexone hydrochloride | SCH 221510 | Matrine | Amentoflavone | Mirtazapine | Mianserin hydrochloride | (-)-Menthol | Bevenopran | Naloxone HCl Dihydrate | Trimebutine |
| 相關(guān)庫 | 經(jīng)典已知活性庫 | 已知活性化合物庫 | ReFRAME 相關(guān)化合物庫 | GPCR靶點(diǎn)分子庫 | 膜蛋白靶向化合物庫 | 神經(jīng)退行性疾病化合物庫 | 疼痛相關(guān)化合物庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |