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+.