Chlorpromazine

Chlorpromazine (CPZ) is a phenothiazine acting as dopamine antagonist.Chlorpromazine is a low-potency typical antipsychotic agent for the treatment of psychotic disorders such as schizophrenia.Chlorpromazine (CPZ) is a phenothiazine acting as dopamine antagonist. Aside from application in schizophrenia therapy, chlorpromazine is found to be a putative inhibitor of proteins involved in cancers, heritable autism disorder and prion diseases. Four new β-lactoglobulin variants with double or triple substitutions: I56F/L39A, F105L/L39A, I56F/L39A/M107F or F105L/L39A/M107F changing the shape of the binding pocket were produced and their chlorpromazine binding properties have been investigated by X-ray crystallography, circular dichroism, isothermal titration calorimetry and thermophoresis. The CD spectra and crystal structures revealed that mutations do not affect the protein overall structure but in comparison to WT protein, variants possessing I56F substitution had lower stability while mutation F105L increased melting temperature of the protein. The new variants showed affinity to chlorpromazine in the range 4.2-15.4 10 M. The CD spectra and crystal structures revealed complementarity of the binding pocket shape, to only one chlorpromazine chiral conformer. The (aR)-CPZ was bonded to variants containing I56F substitution while variants with F105L substitution preferred (aS)-CPZ.(In Vitro):Chlorpromazine (0, 10, 20, 40 μM; 0, 24, 48 h) inhibits growth of U-87MG glioma cells in a dose- and time- dependent manner.Chlorpromazine (20 μM; 0, 12, 24, 48 h) decreases the levels of cyclin A and cyclin B1 in U-87MG glioma cells, 12 h later.Chlorpromazine (20 μM) causes inhibition of cell cycle progression.Chlorpromazine (10 μM; 1 h) significantly suppresses the sEV internalization and dramatically reduces MDSCs in sEV-treated bone marrow cells (MDSCs can significantly suppress the immune cell response, causing immunosuppression in cancer cells).Chlorpromazine (3, 10, 20, 40, 60 μM) blocks the hNav1.7 current in a concentration-dependent manner.Chlorpromazine blocks HERG potassium channels with an IC50 value of 21.6 μM and a Hill coefficient of 1.11.(In Vivo):Chlorpromazine (20 mg/kg; i.p.; single daily for 7 days) inhibits xenograft tumor growth in nude mouse.