Liposome-prilocaine interaction mapping evaluated through STD NMR and molecular dynamics simulations
Luís F Cabeça1, Mónica Pickholz, Eneida de Paula
1Institute of Chemistry, UNICAMP, CP 6154, 13083-970 Campinas, SP, Brazil.
The Journal of Physical Chemistry. B
|February 3, 2009
Summary
Prilocaine (PLC) interacts differently with lipid bilayers based on its charge. Protonated PLC prefers the bilayer surface, while neutral PLC inserts deeper, influencing its anesthetic potency.
Area of Science:
- Biochemistry
- Pharmacology
- Physical Chemistry
Background:
- Local anesthetics like prilocaine (PLC) are weak bases.
- Their ionization state influences their interaction with biological membranes.
- Understanding these interactions is crucial for drug design and efficacy.
Purpose of the Study:
- To investigate the interaction of neutral and protonated prilocaine (PLC) with phosphatidylcholine (PC) bilayers.
- To elucidate how ionization affects PLC's membrane localization and orientation.
- To correlate membrane interactions with potential effects on anesthetic potency.
Main Methods:
- Combined experimental (1H NMR, DOSY, STD) and theoretical (molecular dynamics simulations) approaches.
- Quantified association constants of protonated and neutral PLC with liposomes.
- Visualized PLC orientation and insertion depth within simulated bilayers.
Main Results:
- Association constants differed: Ka = 21 L/mol for neutral PLC and Ka = 9 L/mol for protonated PLC with egg PC liposomes.
- STD experiments revealed pH-dependent saturation patterns, with aromatic moiety enhancement at pH 5.5.
- Molecular dynamics showed protonated PLC at the polar interface and neutral PLC inserted deeper and non-oriented.
Conclusions:
- Ionization state dictates prilocaine's (PLC) membrane interaction site and orientation.
- Protonated PLC associates with the bilayer surface, while neutral PLC inserts deeper.
- These distinct membrane interactions likely modulate PLC's access to voltage-gated sodium channels, influencing anesthetic potency.
