STRUCTURE-ACTIVITY-RELATIONSHIPS OF ASTEMIZOLE DERIVATIVES FOR INHIBITION OF STORE OPERATED CA2+ CHANNELS AND EXOCYTOSIS

The effects of a series of analogues of the antiallergic drug astemizo le on the exocytosis of the enzyme beta-hexosaminidase were studied in a mast cell model, the rat basophilic leukemia (RBL-2H3) cell. Beside s differences in the effects on Fc epsilon RI receptor-stimulated exoc ytosis, changes were also observed in Ca2+ influx and in the perturbat ion of the cell membrane. A strong correlation was found between the e ffects on antigen- and thapsigargin-stimulated Ca-45(2+) influx. Furth ermore, the inhibition of Ca-45(2+) influx was correlated with the inh ibition of beta-hexosaminidase release and membrane stabilization. It is concluded that the astemizole analogues are capable of inhibiting m ast cell beta-hexosaminidase release through inhibition of Ca2+-store- operated Ca2+ channels (SOC). Compounds with high lipophilicity also r eleased Ca2+ from intracellular stores. Lowering of the hydrophobicity by introduction of nitrogens or truncation at different sites in the astemizole structure decreased inhibitory activity on SOC channels. Th e inhibition of SOC channels cannot completely be ascribed to non-spec ific membrane effects. The pjperidinyl-benzimidazole moiety was found to be important for inhibition of SOC channels. The observed differenc es in activity possibly depend on the way the compounds penetrate the membrane bilayer. Astemizole is an interesting new tool to study SOC c hannels and can be a lead for the design of mast cell-stabilizing anti allergic drugs. (C) 1998 Elsevier Science B.V. All rights reserved.