NOVEL POTENT INHIBITOR OF RECEPTOR-ACTIVATED NONSELECTIVE CATION CURRENTS IN HL-60 CELLS

A pharmacological classification of receptor-activated nonselective ca tion channels has not been possible because of the lack of specific an d potent pharmacological blockers. In dibutyryl-cAMP-differentiated HL -60 cells, we recently identified ATP- and N-formyl-L-methionyl-L-leuc yl-L-phenylalanine (fMLP)-stimulated cation currents that were blocked by an organic inhibitor of receptor-mediated Ca2+ entry, xyphenyl)-pr opoxy]-4-methoxyphenethyl-1H-imidazole hydrochloride (SK&F 96365), wit h an IC50 of about 3 muM. Here, we describe a new compound, -N,N-di-[2 -(2,3,4-trimethoxyphenyl)ethyl]acetamide (LOE 908), that fully blocked these currents at 3 muM. Half-maximal inhibition of agonist-activated nonselective inward currents was seen at 40 nm LOE 908, whereas volta ge-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 expo sed to 3 muM LOE 908. The rank order of potency of cations blocking AT P- and fMLP-induced inward currents was Gd3+ > Ni2+ > Cd2+.