EFFECTS OF TETRANDRINE AND CLOSELY RELATED BIS‐BENZYLISOQUINOLINE DERIVATIVES ON CYTOSOLIC Ca2+ IN HUMAN LEUKAEMIC HL‐60 CELLS: A STRUCTURE‐ACTIVITY RELATIONSHIP STUDY

1. Previously it has been shown that tetrandrine (TET), a bis-benzylisoquinoline alkaloid, isolated from a Chinese herb Stephania tetrandra, can block non-voltage-operated Ca2+ entry activated by intracellular Ca2+ store depletion induced by thapsigargin (TSG) and can release intracellular Ca2+ in HL-60 cells. The present study attempted to identify the chemical group(s) of the TET molecule responsible for these dual effects. The effects of TET and its closely related analogues, hernandezine (HER) and berbamine (BER), on Ca2+ entry and Ca2+ release were compared in fura-2-loaded HL-60 cells. 2. Berbamine was much less potent (IC50 = 200 mumol/L) than TET and HER (both IC50 values = 25 mumol/L) in inhibiting Ca2+ entry activated by TSG. Furthermore, at 100 mumol/L, BER was much less effective than TET and HER in suppressing TSG-induced Mn2+ entry. At 30-100 mumol/L, BER was significantly less effective than both TET and HER in causing Ca2+ release from internal stores. However, only BER was able to cause store depletion-activated Ca2+ entry (or the so-called 'capacitative Ca2+ entry') upon Ca2+ readmission. 3. Taken together, the data from this structure-activity relationship study reveal that the -OCH3 group of one particular benzene ring of TET, which distinguishes TET from BER, in part produces the dual pharmacological actions of TET.