Clemastine fumarate

• Catalog No.: S1847
• CAS Number: 14976-57-9
• M. F.: C25H30ClNO5
• M. W.: 459.9624
• Storage: -20°C

SYNONYMS

• IUPAC name: (2E)-but-2-enedioic acid; (2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine
• IUPAC Traditional name: clemastine; fumaric acid
• Synonyms: Tavist; Aloginan; Xolamin; Agasten

DATABASE IDS

• CAS Number: 14976-57-9

PROPERTIES

• Salt Data: Free Base
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Immunology

Biological Activity

• Description: Clemastine Fumarate (Clemastine) is a selective histamine H1 receptor antagonist with IC50 of 3 nM.
• Targets: Histamine H1 receptor
• IC50: 3 nM ^[1]
• In Vitro: Clemastine Fumarate inhibits histamine induced rise in [Ca^2+]_i in HL-60 cells with an IC50 of 3 nM as compared with that of chlorpheniramine or diphenhydramine with IC50 values of 20 nM and 100 nM, respectively. ^[1] At concentrations of ≥25 μM, Clemastine Fumarate significantly blocks NK and ADCC reactions of lymphocytes against the human erythroleukemia cell line K562 and human B-lymphoblast cell line SB, respectively. ^[2] Clemastine Fumarate inhibits histamine-induced contraction of guinea pig ileum with an IC50 of 231 nM. ^[3] Clemastine Fumarate potently inhibits the HERG K^+ channel in a concentration-dependent manner in HEK 293 cells stably expressing HERG channels with an IC50 of 12 nM, which can be attenuated by the Y652A or F656A mutation of HERG. ^[4] Clemastine Fumarate significantly potentiates ATP-induced increase in [Ca^2+]_i in HEKhP2X7 cells not relying on histamine receptor blockage but on sensitizing P2X7 receptor in a concentration-dependent manner with an EC50 of 10 μM, and increases the IL-1β release from LPS-induced human macrophages. ^[5]
• In Vivo: Administration of Clemastine Fumarate (5-20 mg/kg) displays significantly inhibitory effect on simultaneously induced zymosan paw oedema and croton oil ear oedema in rats in a dose-dependent manner, with the inhibition of 53.6% and 46.8%, respectively, at the dose of 20 mg/kg, and with ID50 values of 18.0 mg/kg and 20.5 mg/kg, respectively. ^[6] Clemastine Fumarate treatment strongly reduces innate immune responses to Listeria monocytogenes in mice by interfering with the extracellular signal-regulated kinase (ERK)-mediated production of proinflammatory cytokines such as TNF-α and IL-6 surprisingly not dependent on blocking the histamine H1 receptor, leading to significantly higher mortality. ^[7]
• Clinical Trials: Currently under Phase III study to evaluate the effectiveness of Clemastine Fumarate 1.0 mg/g + dexamethasone 0.5 mg/g compared to dexchlorpheniramine maleate 10 mg/g in eczema treatment

Protocol

• Protocol: Kinase Assay ^[1]
• Inhibition of [Ca2+]i: HL-60 cells are suspended at 1×10^7 cells/mL in a buffer consisting of 138 mM NaCl, 6 mM KC1, 1 mM MgSO4, 1 mM Na₂HPO₄, 5 mM NaHCO₃, 5.5 mM glucose, and 20 mM HEPES-NaOH, pH 7.4, supplemented with 0.1% (w/v) bovine serum albumin. The dye fura-2/AM is added at a concentration of 4 μM, and cells are incubated for 10 minutes at 37 °C. Thereafter, cells are diluted with the aforementioned buffer to a concentration of 5×10^6 cells/mL and incubated for 45 minutes at 37 °C. Subsequently, cells are diluted with the aforementioned buffer to a final concentration of 0.5 × 10^6 cells/mL and centrifuged at 250 g for 10 minutes at 20 °C. Cells are suspended at 1.0 × 10^6 cells/mL in the aforementioned buffer and kept at 20 °C until measurement. HL-60 cells are used for up to 4 hours after loading with fura-2/AM, and suspended in 2 mL of the aforementioned buffer, using acryl fluorescence cuvettes. HL-60 cells are incubated for 3 minutes at 37 °C, in the presence of 1 mM Ca^2+ and various concentrations of Clemastine Fumarate, before the addition of histamine (100 μM). Fluorescence is determined at 37 °C, with constant stirring of the cells at 1×10^3 rpm, using a Ratio II spectrofluorometer. The basal fluorescence (basal [Ca^2+]_i) is measured for 1 minute. The basal [Ca^2+]_i values are subtracted from the corresponding peak [Ca^2+]_i values, to calculate the increase in [Ca^2+]_i. The excitation and emission wavelengths are 340 and 500 nm, respectively. The IC50 value is assessed from competitive curve.
• Protocol: Animal Study ^[6]
• Animal Models: Male Wistar rats with paw oedema induced by subplantar injection of zymosan and ear oedema induced by croton oil
• Formulation: Dissolved in saline
• Doses: 5-20 mg/kg
• Administration: Intraperitoneally

References

• References: [1] Seifert R, et al. Mol Pharmacol, 1992, 42(2), 227-234.
• References: [2] Nair MP, et al. Cell Immunol, 1983, 81(1), 45-60.
• References: [3] Merlos M, et al. J Pharmacol Exp Ther, 1997, 280(1), 114-121.
• References: [4] Ridley JM, et al. J Mol Cell Cardiol, 2006, 40(1), 107-118.
• References: [5] Nörenberg W, et al. J Biol Chem, 2011, 286(13), 11067-11081.
• References: [6] Blazsó G, et al. Pharmacol Res, 1997, 35(1), 65-71.

REFERENCES

• Seifert R, et al. Mol Pharmacol, 1992, 42(2), 227-234.
• Nair MP, et al. Cell Immunol, 1983, 81(1), 45-60.
• Merlos M, et al. J Pharmacol Exp Ther, 1997, 280(1), 114-121.
• Ridley JM, et al. J Mol Cell Cardiol, 2006, 40(1), 107-118.
• Nörenberg W, et al. J Biol Chem, 2011, 286(13), 11067-11081.
• Blazsó G, et al. Pharmacol Res, 1997, 35(1), 65-71.