Phase transition in a lipid bilayer. II. Influence of adamantane derivatives.

The influence of thirty-four adamantane, protoadamantane, and homoadamantane derivatives on the phase transition characteristics of the bilayer in dipalmitoyl lecithin liposomes has been determined by differential scanning calorimetry. Each of these compounds induces a broadening of the phase transition profile of the lipid bilayer that is dependent upon the concentration of the solute and its molecular structure. The concentration--response curves obtained for these solutes suggest that the cage compound derivatives modify the phase properties and under some conditions may induce a phase separation in the doped bilayer. The relative activity sequences obtained for the compounds examined cannot be accounted for by simple considerations of lipid/water partition coefficients, substitution constants based on free energy relationships, or the relative polarities or sizes of substituent groups. The observations are consistent with the hypothesis that the position and orientation of a solute within the bilayer are critical factors in determining its relative potency. The position of a solute within the bilayer is significantly controlled by the presence of polar substituents and by the relative geometric relationships of these groups. For a given substituent group, the shape and size of the hydrocarbon cage becomes increasingly important. It is apparent that seemingly minor modifications in the structure of a solute can significantly alter its influence on the phase transition behavior of a bilayer.