title: Inhibition of inositol-1,4,5-trisphosphate-5-phosphatase by chlorpromazine and related compounds.
abstract: The effects of chlorpromazine and related compounds upon soluble and particulate Ins(1,4,5)P3-5-phosphatase were investigated in rat GH3 pituitary and in human IMR-32 neuroblastoma cells. Chlorpromazine inhibited both soluble and particulate activities with an IC50 of 1 mM after a preincubation time of 10 min at 37 degrees C. The inhibition was time-dependent and could not be reversed by washing the membranes. Inhibition of soluble activity was found at mM concentrations with a number of phenothiazine derivatives with an apparent requirement for a-Cl, an-SCH3 or a-CF3 (compared with an-H or a-COCH3) substituent at the ring position 2. Such a requirement was also seen in other tricyclic compounds, although clozapine was not active and methixene was active. No such requirement was seen for the particulate enzyme.
authors.affiliation: Astra Arcus AB, CNS Preclinical R&D, Södertälje, Sweden.
authors.forename: C J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: G
authors.initials: G
authors.lastname: Brännström
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001932:Brain Neoplasms / Q000201:enzymology; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000031:analogs & derivatives / Q000494:pharmacology*; D005476:Fluphenazine / Q000494:pharmacology; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D009447:Neuroblastoma / Q000201:enzymology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D010902:Pituitary Gland / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000929:Antidepressive Agents, Tricyclic; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D005476:Fluphenazine; D002746:Chlorpromazine