title: Novel potent inhibitor of receptor-activated nonselective cation currents in HL-60 cells.
abstract: A pharmacological classification of receptor-activated nonselective cation channels has not been possible because of the lack of specific and potent pharmacological blockers. In dibutyryl-cAMP-differentiated HL-60 cells, we recently identified ATP- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated cation currents that were blocked by an organic inhibitor of receptor-mediated Ca2+ entry, 1-beta-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenethyl-1H-imidazole hydrochloride (SK&F 96365), with an IC50 of about 3 microM. Here, we describe a new compound, (RS)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-gamma 1)-2-phenyl-N, N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]acetamide (LOE 908), that fully blocked these currents at 3 microM. Half-maximal inhibition of agonist-activated nonselective inward currents was seen at 40 nM LOE 908, whereas voltage-dependent K+ currents in undifferentiated HL-60 cells were blocked with an IC50 of 620 nM. fMLP-induced single-channel currents of 4-5-pS conductance were abolished when the excised inside-out patch was exposed to 3 microM LOE 908. The rank order of potency of cations blocking ATP- and fMLP-induced inward currents was Gd3+ > Ni2+ > Cd2+.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Krautwurst
authors.forename: J
authors.initials: J
authors.lastname: Hescheler
authors.forename: D
authors.initials: D
authors.lastname: Arndts
authors.forename: W
authors.initials: W
authors.lastname: Lösel
authors.forename: R
authors.initials: R
authors.lastname: Hammer
authors.forename: G
authors.initials: G
authors.lastname: Schultz
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002412:Cations / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D004594:Electrophysiology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000081:Acetamides; D002412:Cations; D007473:Ion Channels; D007546:Isoquinolines; C081356:LOE 908; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; D000255:Adenosine Triphosphate