Can protonated β-blockers interact with biomembranes stronger than neutral isolipophilic compounds?

The chromatographic capacity factors (k′) of 10 β-adrenoceptor antagonists (“β-blockers”) were measured on three different immobilized artificial membrane-phosphatidylcholine (IAM-PC) HPLC stationary phases, namely IAM-PC-MG, IAM-PC-DD2, and IAM-PC-DD. The two former phases are made of phosphatidylcholine as found in biomembranes and differ each other in end-capping of free propylamino residues whereas the latter is made of single-chain phosphatidylcholine analogues. On IAM-PC-DD2 we found that structurally unrelated neutral compounds give a single correlation between log k′ values and the respective octanol/water partition coefficients (log P), as previously observed on IAM-PC-MG phase. This was not observed on the IAM-PC-DD phase. IAM chromatography was performed at a pH of the aqueous eluent (7.0) close to the physiological pH 7.4. Retention on all IAM phases showed a biphasic pattern, being proportional to log PN (lipophilicity of neutral forms) for more lipophilic congeners (log PN > 1.90), and quite constant for the others. The comparison of β-blocker retention with that of neutral compounds on IAM-PC-MG and IAM-PC-DD2 suggests that they can interact with phospholipids as strongly or more strongly than neutral isolipophilic compounds, despite their being more than 98% in their ionized form. Therefore, we hypothesize that electrostatic interactions play a pivotal role in the interactions between β-blockers and membrane phospholipids.