NMR Study of the Interaction of Beta-Blockers with Sonicated Dimyristoylphosphatidylcholine Liposomes in the Presence of Praseodymium Cation

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Abstract
The interaction of a series of beta-adrenoreceptor blocking agents with unilamellar dimyristoylphosphatidylcholine (DMPC) liposomes has been studied by proton nuclear magnetic resonance (1H-NMR) in the presence of praseodymium cation (Pr3+) at 30 degrees C. Addition of Pr3+ increased the splitting of the trimethylammonium group signals arising from the phospholipid molecules located at the internal and external surfaces of the bilayers. Adding Pr3+ caused a considerable downfield shift of the external peak but only a slight upfield shift of the internal peak (approximately 3%). The difference in chemical shift of the external and internal peaks (delta Hz) increased linearly as a function of Pr3+ concentration up to 10 mM. The addition of beta-blockers reversed the effect of Pr3+, and propranolol exerted the most pronounced effect, causing complete reversal of the splitting at a concentration of 5 mM. Much higher concentrations of other beta-blockers were required to displace Pr3+. A linear correlation between Pr3+ displacement (P) and logarithm of the apparent partition coefficient (K'm) in DMPC liposomes was obtained for hydrophobic beta-blockers, but hydrophilic beta-blockers did not fit this correlation. It appears that beta-blockers that have ortho or meta substitution require penetration of the liposome bilayers before significant polar group interaction can occur. On the other hand, beta-blockers that have para substitution and low K'm values are able to interact with the polar surfaces of the liposomes without penetration to cause displacement of Pr3+.