| 名稱 | Pimavanserin |
| 描述 | Pimavanserin (ACP-103)(ACP-103) is an effective and specific 5-HT2A receptor inverse agonist (mean pIC50: 8.7, in the cell-based functional assay). Pimavanserin is an atypical antipsychotic used in the treatment of hallucinations and psychosis in patients with Parkinson disease. |
| 細(xì)胞實(shí)驗(yàn) | Pimavanserin (ACP-103) is dissolved in DMSO and stored, and then diluted with appropriate media before use[1]. For the whole-cell binding, 6 million human embryonic kidney 293T cells are plated in 10-cm dishes and transfected with 5 μg of plasmid DNA using Polyfect. Two days after transfection, cells are harvested with 10 mM EDTA, washed, and resuspended in binding buffer (1× DMEM with 0.1% bovine serum albumin). Then, 60,000 cells transfected with the 5-HT2A receptor or 20,000 cells transfected with the 5-HT2C-INI receptor are incubated at 37°C for 3 h in the presence of 5 nM radioligand ([3H]ketanserin for 5-HT2A receptors and [3H]mesulergine for 5-HT2C-INI receptors) and varying concentrations of ligands (total volume 100 μL in a 96-well plate). Cells are filtered onto a 96-well GF/B filter plate and washed with 300 mL of wash buffer (25 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, and 0.25 M NaCl) using a Filtermate 196 harvester. The filter plates are dried under a heat lamp before addition of 50 μL of scintillation fluid to each well. Plates are counted on a TopCount. Separately, the hydrochloride salt form of Pimavanserin (10 μM) is evaluated at MDS Pharma Services for activity in a broad screen of radioligand binding assays at 65 different receptors[1]. |
| 激酶實(shí)驗(yàn) | For the membrane binding, NIH-3T3 cells are grown to 70% confluence in 15 cm2 dishes and transfected with 10 μg of receptor plasmid DNA using Polyfect transfection reagent. Two days after transfection, cells expressing the desired serotonin receptor are homogenized in 20 mM HEPES/10 mM EDTA and spun down at 11,000 g at 4°C for 30 min. The supernatant is discarded, and the pellet is resuspended in 20 mM HEPES/1 mM EDTA and spun down at the same setting. The pellet is then resuspended in 20 mM HEPES/0.5 mM EDTA, and membranes are used for binding assays. Bradford analysis is used to determine total membrane protein. Kd and Bmax values are derived from 12-point concentration experiments using 1 nM [3H]ketanserin for the 5-HT2A receptor and 3 nM [3H]mesulergine for the 5-HT2B and 5-HT2C receptors. Membranes are incubated at room temperature for 3 h with various concentrations of test ligand in the presence of a fixed concentration of radioligand. The suspension is filtered as explained below for whole-cell binding, washed with ice-cold buffer, and dried, and radioactivity is determined using TopCount[1]. |
| 體外活性 | Pimavanserin (ACP-103) 在異源表達(dá)的人類5-HT2A受體上與[3H]ketanserin的結(jié)合發(fā)生競爭性拮抗作用，其平均pKi值在膜中為9.3，在整個細(xì)胞中為9.70。 Pimavanserin 對人類5-HT2C受體顯示出較低的親和力（膜中平均pKi為8.80，整個細(xì)胞中為8.00，通過放射配體結(jié)合測定）和作為反向激動劑的效力較低（R-SAT中平均pIC50為7.1），并且在5-HT2B受體、多巴胺D2受體和其他人類單胺受體上缺乏親和力和功能活性[1]。 Pimavanserin (ACP-103) 對5-HT2A受體具有高度選擇性，對其他受體缺乏親和力，這些受體在包括65種不同分子靶標(biāo)的廣泛篩選中；Pimavanserin 唯一顯示出親和力的其他受體是5-HT2C，根據(jù)測驗(yàn)，Pimavanserin 對5-HT2A受體的選擇性大約是對5-HT2C受體的30倍[2]。 |
| 體內(nèi)活性 | Pimavanserin（ACP-103）是一種強(qiáng)效、有效、口服活性的5-HT2A受體逆向激動劑，具有與抗精神病化合物效用一致的行為藥理學(xué)特征。Pimavanserin 減輕由5-HT2A受體激動劑（±）-2,5-二甲氧基-4-碘苯丙胺 hydrochloride 在大鼠中誘發(fā)的頭擺行為（3 mg/kg p.o.）和預(yù)脈沖抑制缺損（1-10 mg/kg s.c.），并減輕由N-甲基-D-天冬氨酸受體非競爭性拮抗劑5H-二苯并[a,d]環(huán)庚烯-5,10-亞胺（dizocilpine maleate; MK-801）在小鼠中誘發(fā)的過動行為（0.1 和 0.3 mg/kg s.c.; 3 mg/kg p.o.），這與5-HT2A受體作用機(jī)制在體內(nèi)和類似抗精神病化合物的效用一致。Pimavanserin 在大鼠中展示出>42.6%的口服生物利用度[1]。 |
| 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 : 60 mg/mL (140.33 mM)
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| 關(guān)鍵字 | inhibit | Serotonin Receptor | ACP103 | Pimavanserin | 5-HT Receptor | Inhibitor | ACP 103 | 5-hydroxytryptamine Receptor |
| 相關(guān)產(chǎn)品 | Cinchonidine | Sevoflurane | Cloperastine hydrochloride | Alverine citrate | Amitriptyline hydrochloride | Olanzapine | Dapoxetine hydrochloride | Trazodone hydrochloride | Mianserin hydrochloride | Fluoxetine hydrochloride | Serotonin hydrochloride | CLOZAPINE N-OXIDE |
| 相關(guān)庫 | 抗癌上市藥物庫 | 經(jīng)典已知活性庫 | 已知活性化合物庫 | FDA 上市藥物庫 | 神經(jīng)退行性疾病化合物庫 | 疼痛相關(guān)化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |