Interaction of alkyl ammonium derivatives with red cells: Hemolysis and sodium pump inhibition studies

Summary

Members of four homologous series of tetra-alkyl ammonium bromides (R ₃N⁺(CH₂) _n−1·CH₃Br⁻ whereR=H, CH₃ or C₂H₅ andR′N⁺H₃Br⁻ whereR′ represents the isomeric butyl series) have been synthesized and tested as sodium pump inhibitors, measured as ouabain-sensitive K⁺ influx, and as hemolytic agents on human red cells.

Potency for both effects is presented graphically, plotting the logarithm of the concentration for half maximal effect against alkyl chain length. Both hemolysis and pump inhibition studies yielded a biphasic response consisting of two good straight lines, with effectiveness increasing up to C10–12 and then remaining constant up to C20.

For hemolysis the alkyl ammonium series was most effective. The calculated free-energy change per methylene group was the same for three series of compounds, but the free-energy contribution from the headgroup was lower for the ammonium series.

In contrast, although pump inhibition studies also yielded simple biphasic plots, inhibition occurred at 3- to 50-fold lower concentrations and there were significant differences between the three series, both in the free-energy changes per methylene group and in the headgroup contributions.

We have analyzed these results thermodynamically to take account of hydrophobic interactions and the conformation of the alkyl chains.