Membrane interactions and metal ion effects on bilayer permeation of the lipophilic ion modulator DP-109

DP-109, a lipophilic bivalent metal ion modulator currently under preclinical development for neurodegenerative disorders, was designed to have membrane-associated activity, thereby restricting its action to the vicinity of cell membranes. We describe the application of a colorimetric phospholipid/ polydiacetylene (PDA) biomimetic membrane assay in elucidating DP-109 membrane interactions and penetration into lipid bilayers. In this membrane model, visible quantifiable color changes were monitored in studying membrane interactions. The colorimetric data identified a biphasic concentration- dependent interaction, with a break point around the critical micelle concentration (CMC) of DP-109. The kinetics and colorimetric dose-response profile of DP-109 indicate that the compound inserts into the lipid bilayers rather than being localized at the bilayer surface. Analysis of interactions of DP-109 with phospholipid/ PDA vesicles in which ionic gradients were imposed indicates that membrane activity of DP-109 is strongly affected by electrochemical gradients imposed by K^- and Zn²⁺. The ionic gradient effects suggest that the insertion of DP-109 into the membrane may depend on the membrane potential.