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

Abstract

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.

• Authors: Sofiya Kolusheva, Jonathan Friedman, Itzchak Angel, Raz Jelinek
• Journal: Biochemistry (Biochemistry) Vol. 44 Issue 36 Pg. 12077-85 (Sep 13 2005) ISSN: 0006-2960 [Print] United States
• PMID: 16142905 (Publication Type: Journal Article)

Chemical References

• DP-109
• Ions
• Lipid Bilayers
• 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
• Egtazic Acid
• Sodium
• Zinc
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
• Potassium

Topics

• Egtazic Acid (analogs & derivatives, chemistry, pharmacology)
• Ions (chemistry)
• Lipid Bilayers (chemistry, metabolism)
• Molecular Structure
• Potassium (chemistry, pharmacology)
• Sodium (chemistry, pharmacology)
• Zinc (chemistry, pharmacology)