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Research Area
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Description
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Neurological Disease |
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Biological Activity
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Description
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Chlorprothixene has strong binding affinities to dopamine and histamine receptors, such as D1, D2, D3, D5, H1, 5-HT2, 5-HT6 and 5-HT7, with Ki of 18 nM, 2.96 nM, 4.56 nM, 9 nM, 3.75 nM, 9.4 nM, 3 nM and 5.6 nM, respectively. |
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Targets
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D1 |
D2 |
D3 |
D5 |
H1 |
5-HT2 |
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IC50 |
18 nM (Ki) |
2.96 nM (Ki) |
4.56 nM (Ki) |
9 nM (Ki) |
3.75 nM (Ki) [1] |
9.4 nM (Ki) [2] |
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In Vitro
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Chlorprothixene exerts strong binding affinities to the dopamine and histamine receptors, such as D1, D2, D3, D5 and H1 with Ki values of 18nM, 2.96 nM, 4.56 nM, 9 nM and 3.75 nM, respectively, but has little affinity to H3 (Ki >1000 nM). [1] Chlorprothixene also shows high affinities for both rat 5-HT6 from stably transfected HEK-293 cells, and rat 5-HT7 receptors from transiently expressed COS-7 cells, with Ki values of 3 nM and 5.6 nM, respectively. [2] Administration of chlorprothixene results in inhibition of SARS-CoV replication in Vero 76 cells, with IC50 of 16.7 μM for Urbani strain, 13.0 μM for Frankfurt-1, 18.5 μM for CHUK-W1 and 15.8 μM for Toronto-2. There are similar to those detected with promazine [3] |
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In Vivo
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Chlorprothixene blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain depressing the release of hypothalamic and hypophyseal hormones. High dose of chlorprothixene inhibits the protection afforded by iproniazid against the reserpine-induced release of catecholamines in adrenal medulla and brain as well as the decrease of 5HT, NE and DA due to reserpine or iproniazid in rat brain. [4] Administration of Chlorprothixene restores normal ceramide concentrations in murine bronchial epithelial cells, reduces inflammation in the lungs of mice with cystic fibrosis (CF) and prevents infection with Pseudomonas aeruginosa, by inhibiting acidsphingomyelinase (Asm) and not neutral sphingomyelinase (Nsm). [5] |
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Clinical Trials
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Under clinical trails for studying the prevention of relapse in Schizophrenia. |
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Features
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Chlorprothixene is the first, typical antipsychotic drug of the thioxanthene class to be synthesized. |
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Protocol
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Kinase Assay
[2]
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| Radioligand binding assay |
COS-7 cells transfected with p5HT7 or pSVK3-5HT1C and HEK-293 cells that express the 5-HT6 receptor are washed with PBS twice for 10 minutes each and then harvested with a cell scraper into 20 mL PBS. After concentration by centrifugation, cells are lysed in binding buffer (50 mM Tris-HCl, pH 7.4) and membranes are collected by centrifugation. [3H]-LSD binding assays for 5-HT6 and 5-HT7 are performed in a total volume of 0.2 or 0.5 mL, respectively, at 25 °C for 90 minutes in the dark. After incubation, the membranes are collected onto polyethyleneimine-pretreated glass fiber filters, washed with 5 mL of ice-cold binding buffer three times and then quantified by liquid scintillation spectrophotometry. Quenching is corrected by the sample channels ratio technique. Nonspecific binding is determined with 10 μM clozapine and represented at least 95% of total binding. Competition and saturation binding data are analyzed by using the LIGAND program. |
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Animal Study
[5]
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| Animal Models |
B6.129P2 (CF/3)-CftrTgH(neoim)Hgu (abbreviated CFMHH) congenic mice. |
| Formulation |
Dissolved in 0.9% NaCl solution, final concentration 8 mg/L |
| Doses |
1 mL every time |
| Administration |
Five 10-minute inhalations, every 12 hours |
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References |
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[1] von Coburg Y, et al. Bioorg Med Chem Lett. 2009, 19 (2), 538-542.
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[2] Roth BL, et al. J Pharmacol Exp Ther. 1994, 268 (3), 1403-1410.
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[3] Barnard DL, et al. Antiviral Res. 2008, 79 (2), 105-113.
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[4] GEY KF, et al. J Pharmacol Exp Ther. 1961, 133, 18-24.
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[5] Becker KA, et al. Am J Respir Cell Mol Biol, 2010, 42(6), 716-724.
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