DISCRIMINATION OF LOCAL ANESTHETIC STEREOISOMERS BY THEIR ENANTIOSPECIFIC INTERACTIVITIES WITH CHIRAL MEMBRANE LIPIDS

Hironori Tsuchiya


Department of Dental Basic Education, Asahi University School of Dentistry, 1851 Hozumi, Mizuho, Gifu 501-0296, Japan

Abstract:

Background: Since the pharmacotoxicological properties of drugs significantly differ depending on their stereostructures, one enantiomer is preferred over its antipode and racemate for decreasing the adverse effects of drug stereoisomers. While the structure-specific interactions of drugs with receptors, channels and enzymes are emphasized as the mode of enantioselective action, the stereospecificity of membrane lipids has not been fully explored. The membrane interactivities of cardiotoxic stereoisomers were compared to get a novel clue to investigate less toxic drugs.

Methods: Local anesthetic bupivacaine and ropivacaine (S(-)-, racemic and R(+)-, 5-200 µM for each) were reacted with biomimetic lipid bilayer membranes which were prepared with cardiolipin, different phospholipids and chiral steroids of varying compositions, followed by measuring fluorescence polarization to determine their comparative membrane interactivities.

Results: All the tested stereoisomers acted on lipid bilayers to modify the membrane fluidity as one of cardiotoxic mechanisms. By increasing its membrane composition (0-40 mol%), cholesterol with several chiral centers produced stereospecific membrane interactions of local anesthetics with the potency of being R(+)-enantiomer > racemate > S(-)- enantiomer at cardiotoxically-relevant concentrations, which agreed with their relative cardiotoxic effects. 5α-Cholestan- 3β-ol also showed the same membrane interactivity of being R(+)-bupivacaine > racemic bupivacaine > S(-)- bupivacaine as cholesterol (3β-cholest-5-en-3-ol). On the other hand, 5β-cholestan-3α-ol showed the reversed rank order of membrane interactivity to be S(-)-bupivacaine > racemic bupivacaine > R(+)-bupivacaine. Neither the membranes consisting of an equimolar mixture of 5α-cholestan-3β-ol and 5β-cholestan-3α-ol nor the membranes without containing any chiral steroids could discriminate bupivacaine stereoisomers.

Conclusion: The opposite configurations are likely to allow drug enantiomers to be discriminated by stereospecifically interacting with chiral lipid molecules in biomembranes. The present results support the clinical use of S(-)-enantiomers for reducing the cardiotoxicity of local anesthetics and may provide a possible mechanistic index for developing less toxic drugs.