| Abstract
| - DP-109, a lipophilic bivalent metal ion modulator currently under preclinical developmentfor neurodegenerative disorders, was designed to have membrane-associated activity, thereby restrictingits 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 andpenetration into lipid bilayers. In this membrane model, visible quantifiable color changes were monitoredin studying membrane interactions. The colorimetric data identified a biphasic concentration-dependentinteraction, with a break point around the critical micelle concentration (CMC) of DP-109. The kineticsand colorimetric dose−response profile of DP-109 indicate that the compound inserts into the lipid bilayersrather 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 stronglyaffected by electrochemical gradients imposed by K+ and Zn2+. The ionic gradient effects suggest thatthe insertion of DP-109 into the membrane may depend on the membrane potential.
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