The thermodynamics of the partitioning of ionizing molecules between aqueous buffers and phospholipid membranes

Purpose. To study the thermodynamics of partitioning of eight ionising dual D-2-recepto beta(2)-adrenoceptor agonists between vesicles of L-alpha-dimyristoylphosphatidylcholine (DMPC) and aqueous buffers. Methods. The thermodynamics of partitioning have been studied by isothermal titration calorimetry (ITC). Results. Compounds which are predominantly cationic at pH 7.4 (designated as class 1 compounds) have a more exothermic partitioning than those which are predominantly in the electronically neutral form (designated as class 2 compounds) at pH 7.4, and less positive standard entropies of partitioning. Under acidic conditions (pH 4.0), class compounds 2 (predominantly electronically neutral at pH 7.4) are almost completely cationic and accordingly have a more exothermic partitioning than at pH 7.4. The standard entropies of partitioning also depend on the pH. When the compounds are predominantly cationic, the standard entropy change is less positive (less favourable) than under conditions where the compounds are predominantly electronically neutral. Conclusions. The observations are consistent with the notion of there being a favourable electrostatic interaction (enthalpically) between the positively charged amino-group of predominantly cationic compounds and the negatively charged phosphate group of the vesicle.